EP2772480B2 - Inhibiteur de la réplication du vih - Google Patents

Inhibiteur de la réplication du vih Download PDF

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Publication number
EP2772480B2
EP2772480B2 EP12844636.6A EP12844636A EP2772480B2 EP 2772480 B2 EP2772480 B2 EP 2772480B2 EP 12844636 A EP12844636 A EP 12844636A EP 2772480 B2 EP2772480 B2 EP 2772480B2
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Prior art keywords
substituted
unsubstituted
aromatic
hydrogen atom
group
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German (de)
English (en)
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EP2772480A4 (fr
EP2772480B1 (fr
EP2772480A1 (fr
Inventor
Tsutomu Iwaki
Kenji Tomita
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
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    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to a novel compound having an antiviral action, in more detail, an anti-HIV drug.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • reverse transcriptase inhibitors AKT, 3TC, etc.
  • protease inhibitors Inavir, etc.
  • integrase inhibitors raltegravir, etc.
  • anti-HIV drugs In addition, in the treatment of AIDS, because resistant viruses easily emerge, it is reported that, multiple drug therapy is currently effective.
  • anti-HIV drugs three types of reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors have been used clinically, but the agents having the same mechanism of action often exhibit cross-resistance, or merely show additive effects, and there is a demand for the development of anti-HIV drugs having a different mechanism of action.
  • Patent Document 1 a compound having a carboxymethyl benzene skeleton as an HIV reverse transcriptase inhibitor has been reported.
  • carboxymethyl pyridine derivatives Patent Documents 2 to 8
  • carboxymethyl pyrimidine derivatives Patent Documents 9 to 11
  • phenylacetic acid derivatives Patent Documents 12 to 13
  • a tricyclic carboxymethyl pyridine derivative Patent Document 14
  • a carboxymethyl pyridone derivative Patent Document 15
  • Patent Document 16 a substituted five-membered ring compound
  • Patent Document 17 a substituted six-membered ring compound
  • Patent Document 18 and Non-Patent Document 1 describe compounds relatively similar to that of the present invention in structure, but each document relates to an antiepileptic drug and an analytical technique.
  • Non-Patent Documents 2 to 6 describe compounds relatively similar to that of the present invention in structure, but all the documents relate to antibiotics.
  • An object of the present invention is to provide a novel compound having antiviral activity. More preferably, the present invention provides an anti-HIV drug having an inhibitory effect on HIV replication.
  • the present inventors have found a novel HIV replication inhibitor. Furthermore, the present inventors have found that the compound of the present invention and a pharmaceutical containing the same are useful as an antiviral drug (examples: an antiretroviral drug, an anti-HIV drug, an anti-HTLV-1 (Human T cell leukemia virus type 1: human T-cell leukemia virus type 1) drug, an anti-FIV (Feline immunodeficiency virus: feline AIDS virus) drug, an anti-SIV (Simian immunodeficiency virus: simian AIDS virus) drug), particularly an anti-HIV drug, an anti-AIDS drug, a therapeutic agent of the related diseases or the like, thereby accomplishing the present invention.
  • an antiretroviral drug an anti-HIV drug
  • an anti-HTLV-1 Human T cell leukemia virus type 1: human T-cell leukemia virus type 1
  • an anti-FIV Feine immunodeficiency virus: feline AIDS virus
  • an anti-SIV Seimian immunode
  • the compound of the present invention has a replication inhibitory activity on a virus, particularly HIV (example: HIV-1) and a resistant virus thereof. Accordingly, the compound of the present invention is useful in the prevention or treatment of viral infections (example: AIDS) and the like.
  • halogen includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom and a chlorine atom are preferable.
  • alkyl includes a linear or branched hydrocarbon group having 1 to 15 carbon atom(s), preferably 1 to 10 carbon atom(s), more preferably 1 to 6 carbon atom(s), further preferably 1 to 4 carbon atom(s).
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like are exemplified.
  • alkyl methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl are exemplified. In another preferable embodiment, methyl, ethyl, n-propyl, isopropyl and tert-butyl are exemplified.
  • alkenyl includes a linear or branched hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, further preferably 2 to 4 carbon atoms, and one or more double bond(s) at any available position.
  • vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like are exemplified.
  • alkenyl vinyl, allyl, propenyl, isopropenyl and butenyl are exemplified.
  • alkynyl includes a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, further preferably 2 to 4 carbon atoms, and one or more triple bond(s) at any available position.
  • ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are exemplified. These may have further a double bond at any available position.
  • Preferable embodiments of "alkynyl” include ethynyl, propynyl, butynyl, and pentynyl.
  • alkylene includes a linear or branched divalent hydrocarbon group having 1 to 15 carbon atom(s), preferably 1 to 10 carbon atom(s), more preferably 1 to 6 carbon atom(s), most preferably 1 to 4 carbon atom(s).
  • methylene, ethylene, trimethylene, propylene, tetramethylene, panta methylene, hexamethylene and the like are exemplified.
  • alkenylene includes a linear or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 4 carbon atoms, and one or more double bond(s) at any available position.
  • alkenylene includes a linear or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 4 carbon atoms, and one or more double bond(s) at any available position.
  • vinylene, propenylene, butenylene, pentenylene and the like are exemplified.
  • alkynylene includes a linear divalent hydrocarbon group having 2 to 15 carbon atoms, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 4 carbon atoms, and one or more triple bond(s) at any available position.
  • alkynylene ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like are exemplified.
  • aromatic carboyclic group includes a mono-, bi-, or more cyclic aromatic hydrocarbon group.
  • aromatic hydrocarbon group phenyl, naphthyl, anthryl, phenanthryl, and the like are exemplified.
  • phenyl is exemplified.
  • non-aromatic carbocyclic group includes a mono-, bi-, or more cyclic, non-aromatic saturated hydrocarbon group or non-aromatic unsaturated hydrocarbon group.
  • a bi- or more cyclic non-aromatic carbocyclyl includes a fused ring wherein a non-aromatic carbocycle of monocyclic, or two or more rings is fused with a ring of the above "aromatic carbocycle".
  • non-aromatic carbocyclic group also includes a cyclic group having a bridge or a cyclic group to form a spiro ring as follows:
  • a monocyclic non-aromatic carbocyclyl 3 to 16 carbon atoms is preferred, more preferably 3 to 12 carbon atoms, futher preferably 4 to 8 carbon atoms.
  • cycloalkyl, cycloalkenyl, and the like are exemplified.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
  • cycloalkenyl examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
  • non-aromatic carbocyclyl of two or more rings indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, dihydroindenyl and the like are exemplified.
  • aromatic heterocyclyl means a 5-8-membered (preferably 5-6-membered) monocyclic aromatic heterocyclyl, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyl,
  • non-aromatic heterocyclyl means 3-8-membered (preferably 5-6-membered) monocyclic non-aromatic heterocyclyl, indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuryl, benzodioxazolyl, benzodioxanyl and benzomorpholinyl.
  • hydroxyalkyl includes a group wherein hydrogen atom(s) attached to one or more carbon atom(s) of above “alkyl” is (are) replaced with one or more hydroxy group(s).
  • hydroxymethy, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-dihydroxyethyl and the like are exemplified.
  • hydroxymethyl is exemplified.
  • alkyloxy includes a group wherein an oxygen atom is substituted with the above “alkyl”.
  • alkyloxy includes a group wherein an oxygen atom is substituted with the above “alkyl”.
  • methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like are exemplified.
  • alkyloxy methyloxy, ethyloxy, n-propyloxy, isopropyloxy and tert-butyloxy are exemplified.
  • alkenyloxy includes a group wherein an oxygen atom is substituted with the above “alkenyl”.
  • vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like are exemplified.
  • alkynyloxy includes a group wherein an oxygen atom is substituted with the above “alkynyl”.
  • alkynyloxy ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like are exemplified.
  • haloalkyl includes a group wherein hydrogen atom(s) attached to one or more carbon atom(s) of the above “alkyl” is (are) replaced with one or more above "halogen".
  • monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like are exemplified.
  • haloalkyl trifluoromethyl and trichloromethyl are exemplified.
  • haloalkyloxy includes a group wherein an oxygen atom is substituted with one above “haloalkyl”.
  • monofluoromethyloxy, monofluoroethyloxy, trifluoromethyloxy, trichloromethyloxy, trifluoroethyloxy, trichloroethyloxy and the like are exemplified.
  • haloalkyloxy trifluoromethyloxy and trichloromethyloxy are exemplified.
  • alkyloxyalkyl includes a group wherein above “alkyl” is substituted with above “alkyloxy”. For example, methyloxymethyl, methyloxyethyl, ethyloxymethyl and the like are exemplified.
  • alkyloxyalkyloxy includes a group wherein above “alkyloxy” is substituted with above “alkyloxy”. For example, methyloxymethyloxy, methyloxyethyloxy, ethyloxymethyloxy, ethyloxyethyloxy and the like are exemplified.
  • alkylcarbonyl includes a group wherein a carbonyl is substituted with one above “alkyl”.
  • alkylcarbonyl includes a group wherein a carbonyl is substituted with one above “alkyl”.
  • methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like are exemplified.
  • alkylcarbonyl methylcarbonyl, ethylcarbonyl and n-propylcarbonyl are exemplified.
  • alkenylcarbonyl includes a group wherein a carbonyl is substituted with one above “alkenyl”.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like are exemplified.
  • alkynylcarbonyl includes a group wherein a carbonyl is substituted with one above “alkynyl”.
  • alkynylcarbonyl ethynylcarbonyl, propynylcarbonyl and the like are exemplified.
  • monoalkylamino includes a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with above “alkyl”.
  • alkyl For example, methylamino, ethylamino, isopropylamino and the like are exemplified.
  • dialkylamino includes a group wherein two hydrogen atoms attached a nitrogen atom of an amino group are replaced with two above “alkyl”. These two alkyl groups may be the same or different. For example, dimethylamino, diethylamino, N,N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like are exemplified.
  • dialkylamino dimethylamino and diethylamino are exemplified.
  • alkylsulfonyl includes a group wherein a sulfonyl is substituted with one above “alkyl”.
  • alkylsulfonyl methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like are exemplified.
  • alkylsulfonyl methylsulfonyl and ethylsulfonyl are exemplified.
  • alkenylsulfonyl includes a group wherein a sulfonyl is substituted with one above “alkenyl”.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like are exemplified.
  • alkynylsulfonyl includes a group wherein a sulfonyl is substituted with one above “alkynyl”.
  • alkynyl ethynylsulfonyl, propynylsulfonyl and the like are exemplified.
  • monoalkylcarbonylamino includes a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with above “alkylcarbonyl”.
  • alkylcarbonyl methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like are exemplified.
  • dialkylcarbonylamino includes a group wherein two hydrogen atoms attached to a nitrogen atom of an amino group are replaced with above “alkylcarbonyl”.
  • the two "alkylcarbonyl” are identical or different.
  • dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino, and the like are exemplified.
  • dialkylcarbonylamino dimethylcarbonylamino and diethylcarbonylamino are exemplified.
  • monoalkylsulfonylamino includes a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with above “alkylsulfonyl”.
  • alkylsulfonyl For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like are exemplified.
  • dimethylsulfonylamino includes a group wherein two hydrogen atoms attached to a nitrogen atom of an amino group are replaced with above “alkylsulfonyl”.
  • dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like are exemplified.
  • dialkylsulfonylamino dimethylsulfonylamino and diethylsulfonylamino are exemplified.
  • alkylimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkyl”.
  • alkyl a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkyl”.
  • alkenylimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkenyl”.
  • alkenyl ethylenylimino, propenylimino and the like are exemplified.
  • alkynylimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkynyl”.
  • alkynylimino ethynylimino, propynylimino and the like are exemplified.
  • alkylcarbonylimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkylcarbonyl”.
  • alkylcarbonylimino methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like are exemplified.
  • alkenylcarbonylimine includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkenylcarbonyl”.
  • alkenylcarbonyl ethylenylcarbonylimino, propenylcarbonylimino and the like are exemplified.
  • alkynylcarbonylimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkynylcarbonyl”.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like are exemplified.
  • alkyloxyimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkyloxy”.
  • alkyloxy methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like are exemplified.
  • alkenyloxyimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkenyloxy”.
  • alkenyloxy ethylenyloxyimino, propenyloxyimino and the like are exemplified.
  • alkynyloxyimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with above “alkynyloxy”.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like are exemplified.
  • alkylcarbonyloxy includes a group wherein an oxygen atom is substituted with one above “alkylcarbonyl”.
  • alkylcarbonyl methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like are exemplified.
  • alkylcarbonyloxy methylcarbonyloxy and ethylcarbonyloxy are exemplified.
  • alkenylcarbonyloxy includes a group wherein an oxygen atom is substituted with one above “alkenylcarbonyl”.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like are exemplified.
  • alkynylcarbonyloxy includes a group wherein an oxygen atom is substituted with one above “alkynylcarbonyl”.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like are exemplified.
  • alkyloxycarbonyl includes a group wherein a carbonyl is substituted with one above “alkyloxy”.
  • alkyloxycarbonyl includes a group wherein a carbonyl is substituted with one above “alkyloxy”.
  • methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like are exemplified.
  • alkyloxycarbonyl methyloxycarbonyl, ethyloxycarbonyl and propyloxycarbonyl are exemplified.
  • alkenyloxycarbonyl includes a group wherein a carbonyl is substituted with one above “alkenyloxy”.
  • alkenyloxy ethylenyloxycarbonyl, propenyloxycarbonyl and the like are exemplified.
  • alkynyloxycarbonyl includes a group wherein a carbonyl is substituted with one above “alkynyloxy”.
  • alkynyloxycarbonyl ethynyloxycarbonyl, propynyloxycarbonyl, and the like are exemplified.
  • alkylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with one above “alkyl”.
  • alkylsulfanyl methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, tert-butylsulfanyl, isobutylsulfanyl and the like are exemplified.
  • alkenylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of sulfanyl is replaced with one above “alkenyl”.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like are exemplified.
  • alkynylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of sulfanyl is replaced with one above “alkynyl”.
  • alkynyl ethynylsulfanyl, propynylsulfanyl, and the like are exemplified.
  • alkylsulfinyl includes a group wherein a sulfinyl is substituted with one above “alkyl”.
  • alkylsulfinyl methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like are exemplified.
  • alkenylsulfinyl includes a group wherein a sulfinyl is substituted with one above “alkenyl”.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl, and the like are exemplified.
  • alkynylsulfinyl includes a group in which a sulfinyl is substituted with one above “alkynyl”.
  • alkynyl ethynylsulfinyl, propynylsulfinyl and the like are exemplified.
  • monoalkylcarbamoyl includes a group wherein a hydrogen atom attached to a nitrogen atom of a carbamoyl group is replaced with above “alkyl”.
  • methylcarbamoyl, ethylcarbamoyl and the like are exemplified.
  • dialkylcarbamoyl includes a group wherein two hydrogen atoms attached to a nitrogen atom of a carbamoyl group are replaced with two above “alkyl”. These two alkyl groups may be the same or different. For example, dimethylcarbamoyl, diethylcarbamoyl, and the like are exemplified.
  • monoalkylsulfamoyl includes a group wherein a hydrogen atom attached to a nitrogen atom of a sulfamoyl is replaced with one above “alkyl”.
  • alkyl For example, methylsulfamoyl and the like are exemplified.
  • dialkylsulfamoyl includes a group wherein two hydrogen atoms attached to a nitrogen atom of a sulfamoyl are replaced with two above “alkyl”. These two alkyl groups may be the same or different. For example, dimethylcarbamoyl, diethylcarbamoyl and the like are exemplified.
  • trialkylsilyl includes a group wherein a silicon atom is substituted with three above “alkyl”. These three alkyl groups may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like are exemplified.
  • aromatic carbocyclyl alkyl includes an alkyl substituted with one or more above “aromatic carbocyclyl”. Examples thereof include such as benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl and a group of the formula of
  • aromatic carbocyclyl alkyl benzyl, phenethyl and benzhydryl are exemplified.
  • non-aromatic carbocyclyl alkyl includes an alkyl substituted with one or more above “non-aromatic carbocyclyl”. Also, “non-aromatic carbocyclyl alkyl” includes a “non-aromatic carbocyclyl alkyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”. Examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and a group of the formula of
  • aromatic heterocyclyl alkyl includes an alkyl substituted with one or more above “aromatic heterocyclyl”. Also, “aromatic heterocyclyl alkyl” includes an "aromatic heterocyclyl alkyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl", and/or "non-aromatic carbocyclyl".
  • Examples thereof include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl and groups of the formula of
  • non-aromatic heterocyclyl alkyl includes an alkyl substituted with one or more above “non-aromatic heterocyclyl”. Also, “non-aromatic heterocyclyl alkyl” includes a “non-aromatic heterocyclyl alkyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl”. Examples thereof include tetrahydropyranylmethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl and groups of the formula of
  • aromatic carbocyclyl alkyloxy includes an alkyloxy substituted with one or more above “aromatic carbocyclyl”. Examples thereof include such as benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy and a group of the formula of
  • non-aromatic carbocyclyl alkyloxy includes an alkyloxy substituted with one or more above “non-aromatic carbocyclyl".
  • non-aromatic carbocyclyl alkyloxy includes a “non-aromatic carbocyclyl alkyloxy” wherein the alkyl portion is substituted with one or more above “aromatic carbocyclyl”. Examples thereof include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy and a group of the formula of
  • aromatic heterocyclyl alkyloxy includes an alkyloxy substituted with one or more above “aromatic heterocyclyl”. Also, “aromatic heterocyclyl alkyloxy” includes an "aromatic heterocyclyl alkyloxy” wherein the alkyl portion thereof is substituted with one or more above "aromatic carbocyclyl", and/or "non-aromatic carbocyclyl".
  • Examples thereof include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy and groups of the formula of
  • non-aromatic heterocyclyl alkyloxy includes an alkyloxy substituted with one or more above “non-aromatic heterocyclyl”.
  • non-aromatic heterocyclyl alkyloxy includes a “non-aromatic heterocyclyl alkyloxy” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl”. Examples thereof include tetrahydropyranyimethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy and groups of the formula of
  • aromatic carbocyclyl alkylsulfanyl includes an alkylsulfanyl substituted with one or more above “aromatic carbocyclyl”. Examples thereof include benzylsulfanyl, phenethylsulfanyl, phenylpropynylsulfanyl, benzhydrylsulfanyl, tritylsulfanyl, naphthylmethylsulfanyl and the like.
  • non-aromatic carbocyclylalkylsulfanyl includes an alkylsulfanyl substituted with one or more above “non-aromatic carbocyclyl”.
  • non-aromatic carbocyclyl alkylsulfanyl includes a “non-aromatic carbocyclyl alkylsulfanyl” wherein the alkyl portion is substituted with one or more above “aromatic carbocyclyl”. Examples thereof include cyclopropylmethylsulfanyl, cyclobutylmethylsulfanyl, cyclopentylmethylsulfanyl, and cyclohexylmethylsulfanyl.
  • aromatic heterocyclyl alkylsulfanyl includes an alkylsulfanyl substituted with one or more above “aromatic heterocyclyl”. Also, “aromatic heterocyclyl alkylsulfanyl” includes an “aromatic heterocyclyl alkylsulfanyl” wherein the alkyl portion is substituted with one or more above “aromatic carbocyclyl", and/or "non-aromatic carbocyclyl".
  • Examples thereof include pyridylmethylsulfanyl, furanylmethylsulfanyl, imidazolylmethylsulfanyl, indolylmethylsulfanyl, benzothiophenylmethylsulfanyl, oxazolylmethylsulfanyl, isoxazolylmethylsulfanyl, thiazolylmethylsulfanyl, isothiazolylmethylsulfanyl, pyrazolylmethylsulfanyl, isopyrazolylmethylsulfanyl, pyrrolidinylmethylsulfanyl, benzoxazolylmethylsulfanyl and the like.
  • non-aromatic heterocyclyl alkylsulfanyl includes an alkylsulfanyl substituted with one or more above “non-aromatic heterocyclyl”. Also, “non-aromatic heterocyclyl alkylsulfanyl” includes a “non-aromatic heterocyclyl alkylsulfanyl” wherein the alkyl portion is substituted with one or more above “aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl".
  • Examples thereof include tetrahydropyranylmethylsulfanyl, morpholinylmethylsulfanyl, morpholinylethylsulfanyl, piperidinylmethylsulfanyl, piperazinylmethylsulfanyl and the like.
  • aromatic carbocyclyl alkyloxycarbonyl includes an alkyloxycarbonyl substituted with one or more above “aromatic carbocyclyl”. Examples thereof include benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl and a group of the formula of
  • non-aromatic carbocyclyl alkyloxycarbonyl includes an alkyloxycarbonyl substituted with one or more above “non-aromatic carbocyclyl”.
  • non-aromatic carbocyclyl alkyloxycarbonyl includes a “non-aromatic carbocyclyl alkyloxycarbonyl” wherein the alkyl portion is substituted with one or more above “aromatic carbocyclyl”. Examples thereof include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl and a group of the formula of
  • aromatic heterocyclyl alkyloxycarbonyl includes an alkyloxycarbonyl substituted with one or more above "aromatic heterocyclyl”. Also, “aromatic heterocyclyl alkyloxycarbonyl” includes an “aromatic heterocyclyl alkyloxycarbonyl” wherein the alkyl portion thereof is substituted with one or more above "aromatic carbocyclyl", and/or "non-aromatic carbocyclyl".
  • Examples thereof include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl and groups of the formula of
  • non-aromatic heterocyclyl alkyloxycarbonyl includes an alkyloxycarbonyl substituted with one or more above “non-aromatic heterocyclyl”.
  • non-aromatic heterocyclyl alkyloxycarbonyl includes a “non-aromatic heterocyclyl alkyloxycarbonyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl”. Examples thereof include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy and groups of the formula of
  • aromatic carbocyclyl alkyloxyalkyl includes an alkyloxyalkyl substituted with one or more above “aromatic carbocyclyl”. Examples thereof include benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl and a group of the formula of
  • non-aromatic carbocyclyl alkyloxyalkyl includes an alkyloxyalkyl substituted with one or more above “non-aromatic carbocyclyl”
  • non-aromatic carbocyclyl alkyloxyalkyl includes a "non-aromatic carbocyclyl alkyloxyalkyl” wherein the alkyl portion attached to a non-aromatic carbocycle is substituted with one or more above "aromatic carbocyclyl”. Examples thereof include cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl and a group of the formula:
  • aromatic heterocyclyl alkyloxyalkyl includes an alkyloxyalkyl substituted with one or more above "aromatic heterocyclyl”. Also, “aromatic heterocyclyl alkyloxyalkyl” includes an "aromatic heterocyclyl alkyloxyalkyl" wherein the alkyl portion attached to aromatic heterocycle is substituted with one or more above "aromatic carbocyclyl" and/or "non-aromatic carbocyclyl".
  • Examples thereof include pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyloxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl and groups of the formula of
  • non-aromatic heterocyclyl alkyloxyalkyl includes an alkyloxyalkyl substituted with one or more above “non-aromatic heterocyclyl”.
  • non-aromatic heterocyclyl alkyloxyalkyl includes a "non-aromatic heterocyclyl alkyloxyalkyl” wherein the alkyl portion attached to non-aromatic heterocycle is substituted with one or more above "aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl”. Examples thereof include tetrahydropyranylmethyloxymethyl, morpholmylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl and groups of the formula of
  • aromatic carbocyclyl alkylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “aromatic carbocyclyl alkyl”. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • non-aromatic carbocyclyl alkylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “non-aromatic carbocyclyl alkyl”. Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like.
  • aromatic heterocyclyl alkylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “aromatic heterocyclyl alkyl”.
  • aromatic heterocyclyl alkyl examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • non-aromatic heterocyclyl alkylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “non-aromatic heterocyclyl alkyl”. Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethyamino and the like.
  • aromatic carbocycle portion of "aromatic carbocyclyl oxy”, “aromatic carbocyclyl amino”, “aromatic carbocyclyl carbonyl”, “aromatic carbocyclyl oxycarbonyl”, “aromatic carbocyclyl carbonylamino”, “aromatic carbocyclyl sulfanyl” and “aromatic carbocyclyl sulfonyl” means the aforementioned "aromatic carbocyclyl".
  • aromatic carbocyclyl oxy includes a group wherein an oxygen atom is substituted with one above “aromatic carbocycle”. Examples include phenyloxy, naphthyloxy and the like.
  • aromatic carbocyclyl amino includes a group wherein the nitrogen atom of amino is attached to above “aromatic carbocycle”. Examples include phenylamino, naphthylamino and the like.
  • aromatic carbocyclyl carbonyl includes a group wherein a carbonyl is substituted with one above “aromatic carbocycle”. Examples include phenylcarbonyl, naphthylcarbonyl and the like.
  • aromatic carbocyclyl oxycarbonyl includes a group wherein a carbonyl is substituted with one above “aromatic carbocyclyl oxy”. Examples include phenyloxycarbonyl, naphthyloxycarbonyl and the like.
  • aromatic carbocyclyl carbonylamino includes a group wherein the nitrogen atom of amino is attached to above “aromatic carbocycle carbonyl”. Examples include phenylcarbonylamino, naphthylcarbonylamino and the like.
  • aromatic carbocyclyl sulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with “aromatic carbocycle”. Examples include phenylsulfanyl, naphthylsulfanyl and the like.
  • aromatic carbocyclyl sulfonyl includes a group wherein a sulfonyl is substituted with one above “aromatic carbocycle”. Examples include phenylsulfonyl, naphthylsulfonyl and the like.
  • non-aromatic carbocycle portion of "non-aromatic carbocyclyl oxy", “non-aromatic carbocyclyl amino”, “non-aromatic carbocyclyl carbonyl”, “non-aromatic carbocyclyl oxycarbonyl", “non-aromatic carbocyclyl carbonylamino”, “non-aromatic carbocyclyl sulfanyl” and “non-aromatic carbocyclyl sulfonyl” means the aforementioned "non-aromatic carbocyclyl".
  • non-aromatic carbocyclyl oxy includes a group wherein an oxygen atom is substituted with one above “non-aromatic carbocycle”. Examples include cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like.
  • non-aromatic carbocyclyl amino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “non-aromatic carbocycle”. Examples include cyclopropylamino, cyclohexylamino, cyclohexenylamino, and the like.
  • non-aromatic carbocyclyl carbonyl includes a group wherein a carbonyl is substituted with one above “non-aromatic carbocycle”. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
  • non-aromatic carbocyclyl oxycarbonyl includes a group wherein a carbonyl is substituted with one above “non-aromatic carbocyclyl oxy”. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like.
  • non-aromatic carbocyclyl carbonylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with above “non-aromatic carbocyclecarbonyl”. Examples include cyclopropyicarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino, and the like.
  • non-aromatic carbocyclyl sulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with one above “non-aromatic carbocycle”. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • non-aromatic carbocyclyl sulfonyl includes a group wherein a sulfonyl is substituted with one above “non-aromatic carbocycle”. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like.
  • aromatic heterocycle portion of "aromatic heterocyclyl oxy”, “aromatic heterocyclylamino”, “aromatic heterocyclyl carbonyl”, “aromatic heterocyclyl oxycarbonyl”, “aromatic heterocyclylcarbonylamino”, “aromatic heterocyclyl sulfanyl” and “aromatic heterocyclyl sulfonyl” means the aforementioned "aromatic heterocyclyl” .
  • aromatic heterocyclyl oxy includes a group wherein an oxygen atom is substituted with one above “aromatic heterocycle”. Examples include pyridyloxy, oxazolyloxy and the like.
  • aromatic heterocyclyl amino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with "aromatic heterocycle". Examples include pyridylamino, oxazolylamino and the like.
  • aromatic heterocyclyl carbonyl includes a group wherein a carbonyl is substituted with one above “aromatic heterocycle”. Examples include pyridylcarbonyl, oxazolylcarbonyl and the like.
  • aromatic heterocyclyl oxycarbonyl includes a group wherein a carbonyl is substituted with one above “aromatic heterocyclyl oxy”. Examples include pyridyloxycarbonyl, oxazolyloxycarbonyl and the like.
  • aromatic heterocyclyl carbonylamino includes a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with "aromatic heterocycle”. Examples include pyridylcarbonylamino, oxazolylcarbonylamino and the like.
  • aromatic heterocyclyl sulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with one above “aromatic heterocycle”. Examples include pyridylsulfanyl, oxazolylsulfanyl and the like.
  • aromatic heterocyclyl sulfonyl includes a group wherein a sulfonyl is substituted with one above “aromatic heterocycle”. Examples include pyridylsulfonyl, oxazolylsulfonyl and the like.
  • non-aromatic heterocycle portion of "non-aromatic heterocyclyl oxy", “non-aromatic heterocyclyl amino”, “non-aromatic heterocyclyl carbonyl”, “non-aromatic heterocyclyl oxycarbonyl”, “non-aromatic heterocyclyl carbonylamio”, “non-aromatic heterocyclyl sulfanyl” and “non-aromatic heterocyclyl sulfonyl” means the aforementioned "non-aromatic heterocyclyl".
  • non-aromatic heterocyclyl oxy includes a group wherein an “non-aromatic heterocycle” is attached to an oxygen atom. Examples include piperidinyloxy, tetrahydrofuryloxy and the like.
  • non-aromatic heterocyclyl amino includes a group wherein one hydrogen atom attached to the nitrogen atom of an amino group is replaced with above “non-aromatic heterocycle”. Examples include piperidinylamino, tetrahydrofurylamino and the like.
  • non-aromatic heterocyclyl carbonyl includes a group wherein above “non-aromatic heterocycle” is attached to a carbonyl group.
  • Examples include piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like are exemplified.
  • non-aromatic heterocyclyl oxycarbonyl includes a group wherein “non-aromatic heterocyclyl oxy” is attached to a carbonyl group. Examples include piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like.
  • non-aromatic heterocyclyl carbonylamino includes a group wherein one or two hydrogen atom(s) attached to the nitrogen atom of an amino group is replaced with above “non-aromatic heterocyclecarbonyl”. Examples include piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like.
  • non-aromatic heterocyclyl sulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with one above “non-aromatic heterocycle”. Examples include piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like.
  • non-aromatic heterocyclyl sulfonyl includes a group wherein a “non-aromatic heterocycle” is attached to a sulfonyl group.
  • examples include piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like.
  • Substituent halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbon
  • Substituent halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkyl
  • Substituted or unsubstituted non-aromatic carbocyclyl and “substituted or unsubstituted non-aromatic heterocyclyl” can be substituted with "oxo". Namely, two hydrogen atoms attached to a carbon atom are replaced with oxo as follows:
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be bridged with alkylene, alkenylene, or alkynylene, or form a spiro ring together with another ring such as cycloalkane, cycloalkene, cycloalkyne, oxirane, oxetane, and thiolane, as shown below
  • non-aromatic carbocycle and “non-aromatic heterocycle” of "substituted or unsubstituted non-aromatic carbocycleoxy", “substituted or unsubstituted non-aromatic heterocycleoxy", "substituted or unsubstituted non-aromatic carbocycleamino", "substituted or unsubstituted non-aromatic heterocycle amino", "substituted or unsubstituted non-aromatic carbocyclecarbonyl", “substituted or unsubstituted non-aromatic heterocyclecarbonyl", “substituted or unsubstituted non-aromatic carbocycleoxycarbonyl", "substituted or unsubstituted non-aromatic heterocycleoxycarbonyl", "substituted or unsubstituted non-aromatic heterocycleoxycarbonyl", "substituted or unsubstituted non-aro
  • R 1 is preferably halogen, cyano, nitro, or -X-R 11 (X is a single bond, -O-, -S-, -NR 12 -, -CO-, -SO 2 -, -O-CO-, -CO-O-, -NR 12 -CO-, -CO-NR 12 -, -NR 12 -CO-O-, -NR 12 -CO-NR 13 -, -NR 12 -SO 2 -, or -SO 2 -NR 12 -, R 11 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsub
  • R 11 and R 12 may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • X is preferably a single bond, -O-, -NR 12 -, -SO 2 -, -NR 12 -CO-, -CO-NR 12 -, -NR 12 -CO-O-, -NR 12 -CO-NR 13 -, -NR 12 -SO 2 - or -SO 2 -NR 12 -, and more preferably a single bond.
  • R 1 is more preferably a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted nonaromatic carbocyclic group, further preferably a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or a substituted or unsubstituted aromatic carbocyclic group, further preferably a hydrogen atom, halogen, cyano, or substituted or unsubstituted alkyl, particularly preferably halogen, cyano, or alkyl having 1 to 4 carbon atoms, and most preferably bromo, cyano, or methyl.
  • R 2 is each independently preferably substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, or substituted or unsubstituted alkynylsulfanyl, more preferably substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy, further preferably substituted or unsubstituted alkyloxy, particularly preferably alkyloxy having 1 to 4 carbon atoms, and most preferably tert-butyloxy.
  • n is preferably 1 or 2, and particularly preferably 1.
  • R 3 is preferably a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, further preferably, substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted dihydrobenzofuryl, substituted or unsubstituted chromanyl, or substituted or unsubstituted benzomorpholinyl, and further preferably substituted or unsubstituted phenyl or substituted or unsubstituted chromanyl.
  • R 3 is a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted nonaromatic heterocyclic group in which substituted or unsubstituted benzene is condensed, it is preferred that the aromatic heterocyclic group or nonaromatic heterocyclic group contains at least one oxygen atom.
  • a preferred substituent is halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyl, haloalkyloxy, monoalkylamino, dialkylamino, alkylsulfanyl, alkenylsulfanyl, or alkynylsulfanyl, a more preferred substituent is halogen, hydroxy, amino, alkyl, or alkyloxy, a further preferred substituent is fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, or methyloxy, and a particularly preferred substituent is fluoro, chloro, hydroxy, amino, methyl, or methyloxy.
  • R 3 preferably has any of the following structures.
  • R 31 , R 32 , R 33 , R 34 and R 35 are each independently preferably a hydrogen atom, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, or haloalkyloxy, more preferably a hydrogen atom, halogen, hydroxy, amino, alkyl, or alkyloxy, further preferably fluoro, chloro, bromo, hydroxy, amino, methyl, ethyl, or methyloxy, and particularly preferably fluoro, chloro, hydroxy, amino, methyl, or methyloxy.
  • R 31 and R 32 , R 32 and R 33 , R 33 and R 34 and R 34 and R 35 each independently may be taken together with an adjacent atom to form an aromatic carbocyclic ring, a nonaromatic carbocyclic ring, an aromatic heterocyclic ring, or a nonaromatic heterocyclic ring.
  • the ring may be substituted by halogen, alkyl, or oxo, and a five-membered ring or a six-membered ring is preferred.
  • R 36 is each independently preferably alkyl, alkenyl, alkynyl, or haloalkyl, more preferably alkyl, and particularly methyl, p is preferably any integer of 0 to 6, and more preferably any integer of 0 to 2.
  • X 3 is preferably alkylene, alkenylene, or alkynylene, more preferably alkylene, and particularly preferably methylene, ethylene, or propylene.
  • R 3 is further preferably a group shown below.
  • R 3 is particularly preferably a group shown below.
  • R 3 is preferably a group shown below.
  • R 4 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and most preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom, hydroxy, formyl, carboxy, carbamoyl, carbamoyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstitute
  • R 5 is further preferably substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted aromatic carbocyclic group carbonyl, substituted or unsubstituted nonaromatic carbocyclic group carbonyl, substituted or unsubstituted aromatic heterocyclic group carbonyl, substituted or unsubstituted nonaromatic heterocyclic group carbonyl, or substituted or unsubstituted nonaromatic carbocyclic carbamoyl.
  • a preferred substituent is halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, monoalkylamino, dialkylamino, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, a nonaromatic heterocyclic group, aromatic carbocyclic group alkyl, nonaromatic carbocyclic group alkyl, aromatic heterocyclic group alkyl, or nonaromatic heterocyclic group alkyl, a more preferred substituent is halogen, hydroxy, amino, cyan
  • R 5 when R 5 is crosslinked or a spiro ring is formed, preferably, R 5 is crosslinked by an alkylene, or the spiro ring is formed with a cycloalkyl ring.
  • R 5 is further preferably a group shown below.
  • R 5 is particularly preferably a group shown below.
  • R 5 is further preferably a group shown below.
  • R 5 is particularly preferably a group shown below.
  • Y is preferably a single bond, alkylene, alkenylene, or alkynylene (however, when R 5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, Y is a single bond), more preferably a single bond or alkenylene, further preferably a single bond or vinylene, and particularly preferably a single bond.
  • Y is also more preferably alkylene.
  • R 6 is preferably a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted nonaromatic carbocyclic group, or substituted or unsubstituted alkyloxy, more preferably a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, further preferably substituted or unsubstituted alkyl, or particularly preferably alkyl having 1 to 4 carbon atoms, and particularly preferably methyl.
  • R 7 is preferably halogen, cyano, nitro, or -Z-R 71 (Z is a single bond, -O-, -S-, -NR 72 -, -CO-, -SO 2 -, -O-CO-, -CO-O-, -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NR 73 -, -NR 72 -SO 2 -, or -SO 2 -NR 72 -, R 71 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted
  • R 71 and R 72 may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • Z is preferably a single bond, -O-, -NR 72 -, -SO 2 -, -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NR 73 -, -NR 72 -SO 2 , or -SO 2 -NR 72 -, more preferably a single bond, -NR 72 -, -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NH-, -NR 72 -SO 2 -, or -SO 2 -NR 72 -, and further preferably a single bond, -NR 72 -, -NR 72 -CO-, -NR 72 -CO-O-, -NR 72 -CO-NH-, or -NR 72 -SO 2 -.
  • R 71 is preferably a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted nonaromatic carbocyclic group, and particularly preferably a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, alkyl substituted by 1 to 3 halogens, (e.g., trifluoromethyl), cycloalkyl, or phenyl.
  • R 72 is preferably a hydrogen atom or substituted or unsubstituted alkyl, and more preferably a hydrogen atom or methyl.
  • R 73 is preferably a hydrogen atom.
  • R 7 is further preferably -Z-R 71 (Z is a single bond, -O-, -NR 72 -, -SO 2 -, -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NR 73 -, -NR 72 -SO 2 -, or -SO 2 -NR 72 -,
  • R 71 is a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted nonaromatic carbocyclic group
  • R 72 and R 73 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl), particularly preferably -Z-R 71 (Z is a single bond, -NR 72 -
  • Z is preferably -O-, -SO 2 -, -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NR 73 -, -NR 72 -SO 2 -, or -SO 2 -NR 72 -, more preferably -NR 72 -CO-, -CO-NR 72 -, -NR 72 -CO-O-, -NR 72 -CO-NH-, -NR 72 -SO 2 -, or -SO 2 -NR 72 -, and further preferably -NR 72 -CO-, -NR 72 -CO-O-, -NR 72 -CO-NH-, or -NR 72 -SO 2 -.
  • R 71 is preferably a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted nonaromatic carbocyclic group.
  • Substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group is also preferred.
  • R 7 is further preferably a group shown below.
  • R 7 is particularly preferably a group shown below.
  • R 1 and R 7 may be taken together with an adjacent atom to form ring A.
  • Ring A may be substituted by 1 to a plurality of R A s and preferably 1 to 7 R A s.
  • the compound represented by the formula (I) may be a compound represented by following formula (II).
  • Ring A is preferably an aromatic carbocyclic ring, a nonaromatic carbocyclic ring, an aromatic heterocyclic ring or a nonaromatic heterocyclic ring, and more preferably an aromatic heterocyclic ring or a nonaromatic heterocyclic ring.
  • ring A is preferably a five-membered ring or a six-membered ring.
  • Ring A is further preferably a five-membered or six-membered aromatic heterocyclic ring or nonaromatic heterocyclic ring, and particularly preferably thiazole, oxazole, imidazole, thiadiazole, oxadiazole, triazole, furan, thiophene, pyrrole, isothiazole, isoxazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydropyran, thiane, piperidine, morpholine, thiomorpholine, piperazine, dioxane, hexahydropyrimidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dioxolane, oxazoline, thiazolidine, imidazoline, isothiadiazolidme, or thiadiazolidine, and most preferably thiazole, imidazole
  • Two atoms of the portion in which ring A is fused with a benzene ring of the scaffold are carbon atoms.
  • R A is each independently, preferably halogen, cyano, nitro, oxo, or -X A -R A1 , more preferably halogen, cyano, oxo, or -X A -R A1 , and further preferably oxo or -X A -R A1 .
  • X A is preferably a single bond, -O-, -S-, -NR A2 -, -CO-, -SO 2 -, -O-CO-, -CO-O-, -NR A2 -CO-, -CO-NR A2 -, -NR A2 -CO-O-, -CO-O-NR A2 -, -O-CO-NR A2 -, -NR A2 -O-CO-, -CO-NR A2 -O-, -ONR A2 -CO, -NR A2 -CO-NR A3 -, -NR A2 -SO 2 -, or -SO 2 -NR A2 -, more preferably a single bond, -O-, -S-, -NR A2 -, -CO-, -SO 2 -, -NR A2 -CO-, -CO-NR A2 -, -NR A2 -CO-NR A
  • R A1 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, more preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and further preferably a hydrogen atom,
  • R A2 and R A3 are each independently, preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and when X A is -NR A2 -, -CO-NR A2 -, -CO-O-NR A2 -, -O-CO-NR A2 -, or -SO 2 -NR A2 -, R A1 and R A2 may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and more preferably a hydrogen atom or substituted or unsubstituted alkyl.
  • R A is particularly preferably substituted or unsubstituted alkyl having 1 to 4 carbon atoms (examples: methyl, benzyl), substituted or unsubstituted alkenyl having 1 to 4 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to 4 carbon atoms, substituted or unsubstituted alkylcarbonyl having 1 to 4 carbon atoms, substituted or unsubstituted monoalkylcarbamoyl having 1 to 4 carbon atoms, substituted or unsubstituted monoalkylcarbonylamino having 1 to 4 carbon atoms, substituted or unsubstituted alkylcarbamoylamino having 1 to 4 carbon atoms, hydroxy, amino, oxo, or substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubsti
  • m is preferably an integer of any of 0 to 7, more preferably an integer of any of 0 to 4, and further preferably an integer of any of 0 to 2.
  • R 2 is each independently preferably substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, or substituted or unsubstituted alkynylsulfanyl, more preferably substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy, further preferably substituted or unsubstituted alkyloxy, particularly preferably alkyloxy having 1 to 4 carbon atoms, and most preferably tert-butyloxy.
  • n is preferably 1 or 2, and particularly preferably 1.
  • R 3 is preferably a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, more preferably, substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted dihydrobenzofuryl, substituted or unsubstituted chromanyl, or substituted or unsubstituted benzomorpholinyl, and further preferably substituted or unsubstituted phenyl or substituted or unsubstituted chromanyl.
  • R 3 is a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted nonaromatic heterocyclic group in which substituted or unsubstituted benzene is condensed, it is preferred that the aromatic heterocyclic group or nonaromatic heterocyclic group contains at least one oxygen atom.
  • a preferred substituent is halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyl, monoalkylamino, dialkylamino, alkylsulfanyl, alkenylsulfanyl, or alkynylsulfanyl, a more preferred substituent is halogen, alkyl, or alkyloxy, a further preferred substituent is fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms (examples: methyl, ethyl), or alkyloxy having 1 to 4 carbon atoms (example: methyloxy), and a particularly preferred substituent is chloro or methyl.
  • R 3 is further preferably a group shown below.
  • R 3 is particularly preferably a group shown below.
  • R 4 is preferably a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and most preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom, hydroxy, formyl, carboxy, carbamoyl, carbamoyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstitute
  • a preferred substituent is halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyl, monoalkylamino, dialkylamino, alkylsulfanyl, alkenylsulfanyl, alkenylsulfanyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, a nonaromatic heterocyclic group, aromatic carbocyclic group alkyl, nonaromatic carbocyclic group alkyl, aromatic heterocyclic group alkyl, or nonaromatic heterocyclic group alkyl, a more preferred substituent is halogen, alkyl, or alkylcarbonyl, and a more preferred substituent is halogen
  • R 5 when R 5 is crosslinked or a spiro ring is formed, preferably, R 5 is crosslinked by an alkylene, or the spiro ring is formed with a cycloalkyl ring.
  • R 5 is further preferably a group shown below.
  • R 5 is particularly preferably a group shown below.
  • Y is preferably a single bond, alkylene, alkenylene, or alkynylene, more preferably a single bond or alkenylene, further preferably a single bond or vinylene, and particularly preferably a single bond.
  • R 5 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • Y is a single bond.
  • R 6 is preferably a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl a substituted or unsubstituted nonaromatic carbocyclic group, or substituted or unsubstituted alkyloxy, more preferably substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, further preferably substituted or unsubstituted alkyl, or particularly preferably alkyl having 1 to 4 carbon atoms, and particularly preferably methyl.
  • Preferred embodiments of the compound represented by the formula (I) include 1) to 180) and 201) to 240) as follows.
  • R 2 is replaced by substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, or substituted or unsubstituted alkynylsulfanyl.
  • preferred embodiments include 201) to 240) as follows.
  • R A is each independently halogen, cyano, oxo, or -X A -R A1 (X A is a single bond, -O-, -S-, -NR A2 -, -CO-, -SO 2 -, NR A2 -CO-, -CO-NR A2 -, -NR A2 -CO-NR A3 -, -NR A2 -SO 2 -, or -SO 2 -NR A2 -, R A1 is a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and R A2 and R A3 are each independently a
  • R 5 is replaced by a hydrogen atom, substituted or unsubstituted alkyl, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted nonaromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted nonaromatic carbocyclic carbamoyl, or -NR 51 R 52 (R 51 is substituted or unsubstituted aromatic carbocyclic carbonyl or substituted or unsubstituted nonaromatic carbocyclic carbonyl, and R 52 is a hydrogen atom).
  • other preferred embodiments of the compound represented by the formula (II) include compounds of 201) to 240) described above in which R 2 is replaced by substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, or substituted or unsubstituted alkynylsulfanyl.
  • a characteristic of the compound according to the present invention is to have an inhibitory effect on HIV replication, in which, in the formula (I),
  • a substituted or unsubstituted alkyloxy group is preferably introduced as R 2 in the formula (I), and/or R 4 is a hydrogen atom, thereby having a high inhibitory effect on HIV replication.
  • the compound represented by the formula (I) is not limited to a specific isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, atropisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof.
  • One or more hydrogens, carbons and/or other atoms of the compounds represented by the formula (I) may be substituted by an isotope of hydrogen, carbon and/or other atom.
  • the isotope include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, like 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl.
  • the compound represented by the formula (I) also includes compounds substituted with the isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled materials of the compounds represented by the formula (I).
  • a "radiolabeling method" for producing the "radiolabeled material" is also included in the present invention, and it is useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies and binding assays.
  • the radiolabeled material of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • a tritium-labeled compound represented by the formula (I) can be prepared, for example, by introducing tritium into a particular compound represented by the formula (I) by catalytic dehalogenation using tritium.
  • This method includes reacting a precursor in which the compound represented by the formula (I) is properly substituted with halogen with tritium gas, in the presence of an appropriate catalyst, for example, Pd/C, in the presence or absence of a base.
  • an appropriate catalyst for example, Pd/C
  • a 14 C-labeled compound can be prepared by using a raw material having a 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) include salts of the compound represented by the formula (I) with an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., calcium, barium, etc.), magnesium, a transition metal (e.g., zinc, iron, etc.), ammonia, an organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinolone, etc.) and an amino acid, or salts with an inorganic acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and an organic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic
  • the compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.) and/or a crystalline polymorph, and the present invention also includes various kinds of solvates and crystalline polymorphs.
  • “Solvate” may be coordinated with solvent molecules (e.g., water molecules, etc.) in any number, relative to the compound represented by the formula (I).
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, whereby it may absorb water and the adsorbed water may attach thereto, or it may form a hydrate.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs.
  • the prodrug is a derivative of the compound of the present invention having a group that can chemically or metabolically decompose, and is a compound to be the pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions.
  • the prodrug includes compounds which are converted to a compound represented by the formula (I) in response to enzymatic oxidation, reduction, hydrolysis, or the like, under physiological conditions in vivo, compounds which are converted to a compound represented by the formula (I) by being hydrolyzed by gastric acid or the like, and the like.
  • a method for selecting an appropriate prodrug derivative and a method for producing the same are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985 .
  • the prodrugs themselves may have an activity.
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydrides or by reacting using a condensing agent are exemplified.
  • Examples include CH 3 COO-, C 2 H 5 COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 )COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p-CH 3 -O-PhSO 3 -, PhSO 3 -, p-CH 3 PhSO 3 -, and the like.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, according to the general synthesis method described below.
  • extraction, purification and the like may be performed by a treatment performed in a normal experiment of organic chemistry.
  • R 6 has the same meaning as described above, and L 1 is substituted or unsubstituted alkyl.
  • Compound a1 that is commercially available or synthesized by a known method is reacted with an acid halide or acid anhydride such as acetyl chloride or acetic anhydride, by Friedel-Crafts-acylation, in a solvent of methylene chloride, dichloroethane or the like, in the presence of a Lewis acid such as aluminum chloride, at 0°C to 150°C, and preferably 60°C to 120°C, for 1 hour to 48 hours, and preferably 12 hours to 24 hours, whereby compound a2 can be obtained.
  • an acid halide or acid anhydride such as acetyl chloride or acetic anhydride
  • Friedel-Crafts-acylation such as aluminum chloride
  • compound a2 is reacted at -30°C to 100°C, and preferably at 0°C to 50°C, for 0.5 hours to 48 hours, and preferably 6 hours to 24 hours, whereby compound a3 can be obtained.
  • an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added to compound a3, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, whereby compound a4 can be obtained.
  • R A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group
  • L 2 is boronic acid, a boronic acid ester, an alkyltin, a zinc halide, or the like.
  • Compounds a5, a6, and a7 can be obtained by a coupling reaction of compound a4 with R A -L 2 .
  • Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, and the like are exemplified.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or Pd(dppf) 2 Cl 2
  • a base such as potassium carbonate, sodium carbonate or potassium phosphate
  • boronic acid a boronic acid ester, an alkyltin or a zinc halide that is commercially available or synthesized by a known method
  • R 1 , R 3 , R 4 , R 5 , R 6 , Y and L 1 have the same meaning as described above
  • R 2' is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • L 3 is halogen.
  • a toluene solution of diisobutylaluminum hydride or a tetrahydrofuran solution of lithium aluminum hydride is added to compound a7, and the mixture is reacted at -100°C to 50°C, and preferably at -60°C to 0°C, for 0.5 hours to 10 hours, and preferably 1 hour to 3 hours, whereby compound a8 can be obtained.
  • an oxidant such as a Dess-Martin reagent, manganese dioxide or sulfur trioxide pyridine is added to compound a8, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.5 hours to 10 hours, and preferably 1 hour to 3 hours to be oxidized, whereby compound a9 can be obtained.
  • compound a9 In a solvent such as methylene chloride, dichloroethane or toluene, zinc iodide and TMSCN are added to compound a9, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a10 can be obtained.
  • a solvent such as methylene chloride, dichloroethane or toluene, zinc iodide and TMSCN are added to compound a9, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a10 can be obtained.
  • an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added to compound a10, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, for deprotection of a TMS group, hydrolysis to the carboxylic acid of nitrile group, followed by esterification, whereby compound a11 can be obtained.
  • a base such as sodium hydride, potassium tert-butoxide or sodium methoxide and R 2' -I, R 2' -Br, R 2' -Cl or the like are added to compound a11, and the mixture is reacted at -20°C to 100°C, and preferably at 0°C to 60°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby compound a12 can be obtained.
  • tert-butyl ester and the like can be also obtained by adding 1 to 3 equivalents of a 70% aqueous perchloric acid solution in tert-butyl acetate, and reacting the mixture at 0°C to 60°C, and preferably at 15°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours.
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide is added to compound a12, and the mixture is reacted under a hydrogen atmosphere at 0°C to 50°C, and preferably at 15°C to 25°C, for 0.1 hours to 48 hours, and preferably 1 hour to 24 hours, whereby compound a13 can be obtained.
  • the reaction may be promoted by adding acetic acid, hydrochloric acid or the like.
  • a metal such as iron, zinc or tin is added to compound a12, under acidic conditions of hydrochloric acid or acetic acid, under alkaline conditions of potassium hydroxide or sodium hydroxide, or under neutral conditions of ammonium chloride, and the mixture is reacted at 0°C to 120°C, and preferably at 25°C to 80°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound a13 can be also obtained.
  • a solvent such as dichloromethane, THF, toluene, acetonitrile or DMF
  • bromine or a halogenating reagent such as NBS, NCS and NIS is added to compound a13, and when L 3 is bromo, the mixture is reacted at -30°C to 50°C, and preferably at -10°C to 20°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a14 can be obtained.
  • the mixture is reacted at 10°C to 150°C, and preferably at 60°C to 120°C, for 0.5 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound a14 can be obtained.
  • compound A-1 can be obtained in the same manner as in the fourth step.
  • compound A-1 In a solvent such as methanol, ethanol, THF or DMSO, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is added to compound A-1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound A-2 can be obtained.
  • a solvent such as methanol, ethanol, THF or DMSO
  • potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is added to compound A-1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound A-2 can be obtained.
  • compound A-1 In a solvent such as methanol, ethanol, THF or DMSO, hydrochloric acid, TFA or the like is added to compound A-1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound A-2 can be also obtained.
  • a solvent such as methanol, ethanol, THF or DMSO, hydrochloric acid, TFA or the like is added to compound A-1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound A-2 can be also obtained.
  • compound a15 that is commercially available or synthesized by a known method is added, in a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling, and the mixture is reacted at -20°C to 60°C, and preferably at 0°C to 25°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby a nitro compound can be obtained.
  • a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling
  • This compound is reacted in a solvent such as thionyl chloride and phosphorus oxychloride, at 20°C to 120°C, and preferably at 80°C to 100°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, and the solvent is concentrated under reduced pressure, whereby a crude acid chloride can be obtained.
  • a solvent such as thionyl chloride and phosphorus oxychloride
  • a solvent such as thionyl chloride and phosphorus oxychloride
  • compound a17 can be obtained in the same manner as in the fourth step.
  • compound a18 can be obtained in the same manner as in the twelfth step.
  • compound a19 can be obtained in the same manner as in the thirteenth step.
  • compound a20 can be obtained in the same manner as in the fourth step.
  • compound a21 can be obtained in the same manner as in the thirteenth step.
  • compound a22 can be obtained in the same manner as in the fourth step.
  • compound A-1 can be obtained in the same manner as in the seventh to eleventh steps.
  • an amino group protecting reagent such as a tert-butyloxycarbonylating reagent or a trifluoroacetylating reagent such as trifluoroacetyl chloride or trifluoroacetic acid anhydride, and a base such as triethylamine or N-methylmorpholine are added to compound a20, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound a23 that is an amino group protector can be obtained.
  • a base such as triethylamine or N-methylmorpholine
  • compound a24 after reacting in the same manner as in the seventh step to the eleventh step, compound a24 can be obtained in the same manner as in the thirteenth step.
  • compound A-1 can be obtained in the same manner as in the fourth step.
  • compound a26 can be obtained in the same manner as in the thirteenth step.
  • nitric acid, fuming nitric acid or the like is added to compound a26 under ice-cooling, and the mixture is reacted at -20°C to 60°C, and preferably at 0°C to 25°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a27 can be obtained.
  • a phosphine such as tri-tert-butylphosphine, tricyclohexylphosphine or triphenylphosphine
  • a catalyst such as dibenzylideneacetone palladium, palladium acetate or dichlorobistriphenylphosphine palladium, zinc fluoride and separately prepared silyl enol ether (a28) are added to compound a27, and the mixture is reacted at 30°C to 130°C, and preferably at 50°C to 150°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 1 hour, whereby compound a29 can be obtained.
  • a base such as pyridine, lutidine or triethylamine, and a trifluoromethanesulfonylating agent such as trifluoromethanesulfonic anhydride or a comin's reagent are added to compound a29, and the mixture is reacted at -50°C to 50°C, and preferably at -30°C to 30°C, for 0.1 hours to 4 hours, and preferably 0.5 hours to 1 hour, whereby compound a30 can be obtained.
  • compound a31 can be obtained in the same manner as in the fourth step.
  • compound a32 can be obtained in the same manner as in the twelfth step.
  • compound a33 can be obtained in the same manner as in the thirteenth step.
  • compound A-1 can be obtained in the same manner as in the fourth step.
  • a base such as potassium carbonate or sodium carbonate and benzyl bromide or benzyl chloride are added to compound a26, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.5 hours to 24 hours, and preferably 1 hour to 5 hours, whereby compound a34 can be obtained.
  • L 8 of compound a34 is converted to a Grignard reagent or a lithium compound by metal magnesium or n-butyl lithium, and a reagent such as dimethylformamide, N-formyl piperidine, and N-formyl morpholine is added, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a35 can be obtained.
  • a solvent such as diethyl ether or THF
  • compound a36 can be obtained in the same manner as in the ninth step.
  • compound a37 can be obtained in the same manner as in the tenth step.
  • compound a29 can be obtained in the same manner as in the eleventh step.
  • compound a28-1 that is commercially available or synthesized by a known method are added, in a solvent such as THF, diethyl ether or dioxane, or in a mixed solvent thereof, R 2' OH and a metal reagent such as sodium hydride, lithium hydride or potassium hydride, and the mixture is reacted at 20°C to 120°C, and preferably at 40°C to 100°C, for 0.1 hours to 12 hours, and preferably 0.5 hours to 6 hours, whereby compound a28-2 can be obtained.
  • a solvent such as THF, diethyl ether or dioxane
  • R 2' OH and a metal reagent such as sodium hydride, lithium hydride or potassium hydride
  • a base such as potassium carbonate, sodium carbonate or potassium phosphate
  • an alkylating agent such as an alkyl iodide, alkyl bromide or alkyl sulfate are added to compound a28-2, and the mixture is reacted at -30°C to 70°C, and preferably at -10°C to 50°C, for 0.1 hours to 5 hours, and preferably 0.5 hours to 1 hour, whereby compound a28-3 can be obtained.
  • a base such as potassium hexamethyldisilazide, lithium hexamethyldisilazide or lithium diisopropylamide, and a silylating agent such as TMSCl and TMSOTf are added to compound a28-3, and the mixture is reacted at -130°C to -20°C, and preferably at -110°C to -50°C, for 0.1 hours to 5 hours, and preferably 0.5 hours to 1 hour, whereby compound a28 can be obtained.
  • optically active forms of compounds A-1 and A-2 can be synthesized by using compound a28', instead of compound a28.
  • Synthesis of compound a28' is possible by the method shown below. wherein each definition has the same meaning as described above.
  • a reagent such as oxalyl chloride or thionyl chloride and oxazolidinone (a28-4) are added to compound a28-2, and the mixture is reacted at -50°C to 50°C, and preferably at -30°C to 30°C, for 0.1 hours to 4 hours, and preferably 0.5 hours to 1 hour, whereby compound a28-5 can be obtained.
  • compound a28' can be obtained in the same manner as in the forty second step.
  • compound a29 is also possible from compound a28', by the method shown below.
  • Compound a29 to be obtained is an optical isomer.
  • optical isomers of compounds A-1 and A-2 can be synthesized by the method described above. wherein each definition has the same meaning as described above.
  • compound a28-6 can be obtained in the same manner as in the twenty ninth step.
  • a mixed liquid of hydrogen peroxide and an aqueous solution of lithium hydroxide is added to compound a28-6, and the mixture is reacted at -20°C to 10°C, and preferably at -10°C to 10°C, for 0.1 hours to 5 hours, and preferably 0.1 hours to 1 hour, to obtain a carboxylate form, and thereafter, without purification, the carboxylate form is directly esterified by the addition of a R 4 N 2 /diethyl ether solution or the like, whereby compound a29 can be obtained.
  • compound a38 can be obtained in the same manner as in the seventh step.
  • compound a39 can be obtained in the same manner as in the eighth step.
  • compound a40 can be obtained in the same manner as in the ninth step.
  • compound a41 can be obtained in the same manner as in the tenth step.
  • an oxidizing agent such as a Dess-Martin reagent or manganese dioxide is added to compound a41, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 45°C, for 0.5 hours to 5 hours, and preferably 1 hour to 3 hours, whereby compound a42 can be obtained.
  • a (R)-CBS reagent is added to compound a42 as an asymmetric source, and a reducing agent such as catechol borane or 9-borabicyclo[3.3.1]nonane is sequentially added, and the mixture is reacted at -50°C to 0°C, and preferably at -35°C to -10°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a43 can be obtained.
  • a reducing agent such as catechol borane or 9-borabicyclo[3.3.1]nonane
  • compound a44 can be obtained in the same manner as in the eleventh step.
  • R 1 , R 2' , R 8 , R 4 , R 5 , R 6 , Y, L 3 , and L 7 have the same meaning as described above, L 10 is halogen, and L 11 is halogen.
  • compound a45 can be obtained in the same manner as in the seventeenth step.
  • compound a46 can be obtained in the same manner as in the eighteenth step.
  • compound a48 can be obtained in the same manner as in the twentieth step.
  • compound a24 can be obtained in the same manner as in the twenty first step.
  • compound a13 can be obtained in the same manner as in the twentieth step.
  • an optical isomer of compound a12 can be synthesized from compound a4. Furthermore, from the optical isomer of compound a12, optical isomers of compounds A-1 and A-2 can be synthesized by the method described above. wherein each definition has the same meaning as described above.
  • compound a50 can be obtained in the same manner as in the forty seventh step to the fifty third step.
  • compound a11 can be obtained in the same manner as in the fourth step to the sixth step.
  • compound a51 can be obtained in the same manner as in the eleventh step.
  • compound a52 can be obtained in the same manner as in the fifteenth step.
  • Compound a53 can be synthesized by condensing compound a52 with an enantiopure chiral auxiliary compound like R-(+)-4-benzyl-2-oxazolidinone (compound (A)) to produce a diastereomeric mixture and separating the diastereomeric mixture by silica gel column chromatography.
  • compound a52 is dissolved in a solvent such as anhydrous dichloromethane, anhydrous chloroform or anhydrous THF, and thereafter a small amount of anhydrous DMF is added, and a chlorinating reagent such as thionyl chloride or oxalyl chloride is added dropwise at -30°C to 50°C, and preferably at -10°C to 20°C.
  • a solvent such as anhydrous dichloromethane, anhydrous chloroform or anhydrous THF
  • a chlorinating reagent such as thionyl chloride or oxalyl chloride is added dropwise at -30°C to 50°C, and preferably at -10°C to 20°C.
  • the mixture is stirred at -30°C to 50°C, and preferably at -10°C to 20°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours and concentrated, and the obtained foamy solid is dissolved in anhydrous tetrahydrofuran, anhydrous dichloromethane, or the like.
  • a solution of anhydrous tetrahydrofuran, anhydrous dichloromethane or the like of compound (A) is stirred at -100°C to -30°C, and preferably at -80°C to -60°C, a n-BuLi/hexane solution is added, and the mixture is stirred at -100°C to -30°C, and preferably at -80°C to -60°C, for 0.1 hours to 1 hour, and preferably 0.1 hours to 0.5 hours, and is further stirred at -20°C to 60°C, and preferably at 0°C to 30°C, for 0.1 hours to 5 hours, and preferably 0.1 hours to 2 hours.
  • the mixture is mixed with the prepared acid chloride solution at -60°C to -10°C, and preferably at -40°C to -20°C, and then heated to -10°C to 60°C, and preferably to 10°C to 30°C.
  • the mixture is quenched with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane, and then separated and purified by silica gel chromatography, whereby compound a53 can be obtained.
  • a mixed liquid of hydrogen peroxide and an aqueous solution of lithium hydroxide is added to compound a53, and the mixture is reacted at -20°C to 10°C, and preferably at -10°C to 10°C, to obtain a carboxylate form, and thereafter, the carboxylate form is esterified by a diazomethane/diethyl ether solution or the like, whereby compound a44 can be obtained.
  • compound a29-1 that is commercially available or prepared by a known method is added, in a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling, and the mixture is reacted at -20°C to 60°C, and preferably at 0°C to 25°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a29-2 can be obtained.
  • a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling
  • compound a29-2 can be obtained by adding a metal salt such as potassium nitrate or sodium nitrate under ice-cooling in concentrated sulfuric acid, and reacting the mixture at -20°C to 60°C, and preferably at 0°C to 25°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours.
  • a metal salt such as potassium nitrate or sodium nitrate under ice-cooling in concentrated sulfuric acid
  • compound a29-2 In a solvent such as dichloromethane, dichloroethane or toluene, zinc iodide and TMSCN are added to compound a29-2, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a29-3 can be obtained.
  • a solvent such as dichloromethane, dichloroethane or toluene
  • zinc iodide and TMSCN are added to compound a29-2, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a29-3 can be obtained.
  • compound a29-3 can be obtained by reacting a metal salt such as zinc iodide, TMSCI, sodium cyanide or potassium cyanide in a solvent such as acetonitrile and DMF at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours.
  • a metal salt such as zinc iodide, TMSCI, sodium cyanide or potassium cyanide
  • a solvent such as acetonitrile and DMF
  • R 4 OH of compound a29-3 an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, for deprotection of a TMS group, hydrolysis to the carboxylic acid of nitrile group, followed by esterification, whereby compound 1-4 can be obtained.
  • an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, for deprotection of a TMS group, hydrolysis to the carboxylic acid of nitrile group, followed by esterification, whereby compound 1-4 can be obtained.
  • a base such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydride, and benzyl bromide or benzyl chloride are added to compound a29-4, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.5 hours to 24 hours, and preferably 1 hour to 5 hours, whereby compound a29-5 can be obtained.
  • compound a29-5 can be obtained by adding diethyl azodicarboxylate or diisopropyl azodicarboxylate, and benzyl alcohol in a solvent such as tetrahydrofuran, toluene or dichloromethane, and reacting the mixture at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.5 hours to 24 hours, and preferably 1 hour to 5 hours.
  • a solvent such as tetrahydrofuran, toluene or dichloromethane
  • an oxidizing agent such as a Dess-Martin reagent, manganese dioxide or pyridinium chlorochromate is added, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 45°C, for 0.5 hours to 5 hours, and preferably 1 hour to 3 hours, whereby compound a29-6 can be obtained. Also, compound a29-6 can be obtained by general Swern oxidation.
  • a (R)-CBS reagent is added as an asymmetric source, and a reducing agent such as catechol borane or 9-borabicyclo[3.3.1]nonane is sequentially added, and the mixture is reacted at -100°C to 0°C, and preferably at -78°C to -50°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a29-7 can be obtained.
  • a base such as sodium hydride, potassium tert-butoxide or sodium methoxide and R 2' -I, R 2' -Br, R 2' -Cl or the like that is commercially available or prepared by a known method are added to compound a29-7, and the mixture is reacted at -20°C to 100°C, and preferably at 0°C to 60°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby compound a29-8 can be obtained.
  • tert-butyl ester and the like can be also obtained by adding 1 to 3 equivalents of a 70% aqueous perchloric acid solution in tert-butyl acetate, and reacting the mixture at 0°C to 60°C, and preferably at 15°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours.
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide is added to compound a29-8, and the mixture is reacted under a hydrogen atmosphere at 0°C to 60°C, and preferably at 20°C to 40°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound a29 can be obtained.
  • compound a29 can be obtained by adding tribromoboron and trimethylsilyliodide in a solvent such as dichloromethane, dichloroethane or chloroform, and reacting the mixture at -20°C to 100°C, and preferably at 0°C to 30°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours.
  • a solvent such as dichloromethane, dichloroethane or chloroform
  • compound a54 In a solvent such as methylene chloride, toluene or THF, phosphorus tribromide, thionyl bromide or the like is added to compound a8, and the mixture is reacted at -20°C to 120°C, and preferably at 0°C to 60°C, for 0.1 hours to 12 hours, and preferably 1 hour to 4 hours, whereby compound a54 can be obtained.
  • a solvent such as methylene chloride, toluene or THF, phosphorus tribromide, thionyl bromide or the like is added to compound a8, and the mixture is reacted at -20°C to 120°C, and preferably at 0°C to 60°C, for 0.1 hours to 12 hours, and preferably 1 hour to 4 hours, whereby compound a54 can be obtained.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or PdCl 2 (dppf) 2
  • a base such as triethylamine or N-methylmorpholine, and R 4 OH
  • a base such as lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide or sodium hexamethyldisilazide, and R 2 -I, R 2 -Br, R 2 -Cl, or the like are added to compound a55, and the mixture is reacted at -70°C to 50°C, and preferably at -20°C to 20°C, for 1 hour to 24 hours, and preferably 3 hours to 10 hours, whereby compound a56 can be obtained.
  • compound A-3 can be obtained in the same manner as in the twelfth to fourteenth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-4 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5a and R 5a' are each independently substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, wherein R 5a and R 5a' may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or PdCl 2 (dppf) 2
  • a base such as triethylamine or N-methylmorpholine
  • allyl alcohol is added to compound a30, and the mixture is reacted under a carbon monoxide atmosphere at 0°C to 150°C, and preferably at 50°C to 100°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby an allyl ester form can be synthesized.
  • compound A-5 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-6 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf) 2 Cl 2 or Pd(dtbpf)
  • a base such as potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate, and trans-ethynylboronic acid, vinyl boronate, vinyl trialkyltin, or the like are added to compound a30, and the mixture is reacted under a nitrogen atmosphere at 0°C to 150°C, and preferably at 60°C to 120°C, for 0.5 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound a57-1 can be obtained.
  • an ozone gas is passed through compound a57-1 at -100°C to 0°C, and preferably at -78°C to 50°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, and thereafter dimethylsulfide, trimethylphosphite, or the like is added, and the mixture is stirred at the same temperature for 0.1 hours to 3 hours, and preferably 0.5 hours to 1 hour, whereby compound a57-2 can be obtained.
  • potassium permanganate is added to compound a57-2, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a57 can be obtained.
  • compound a57 can be also obtained by adding pyridinium dichromate in a DMF solvent, and reacting the mixture at 0°C to 60°C, and preferably at 20°C to 40°C, for 2 hours to 24 hours, and preferably 6 hours to 12 hours.
  • R 5b is alkyl
  • Q is halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyl, alkyloxy
  • a base such as sodium hydride or cesium carbonate, and halogenated alkyl that is commercially available or prepared by a known method are added to compound a59, and the mixture is reacted at 20°C to 140°C, and preferably at 40°C to 80°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound a60 can be obtained.
  • compound A-7 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-8 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5c is alkyl, alkenyl, alkynyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, or a nonaromatic heterocyclic group.
  • compound a61 can be obtained in the same manner as in the first to sixth steps in "30) Synthesis of Compounds N-1 and N-2" described below.
  • compound A-9 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-10 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5d is substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • compound a62 can be obtained in the same manner as in the first to fifth steps in "31) Synthesis of Compounds O-1 and O-2" described below.
  • compound A-11 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-12 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5e and R 5e' are each independently a hydrogen atom, formyl, carbamoyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl, substituted or unsubstituted alkynylcarbamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstit
  • a base such as sodium carbonate, potassium carbonate, cesium carbonate or potassium phosphate, a substituted amine a63 that is commercially available or prepared by a known method
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf) 2 Cl 2 or tris(dibenzylideneacetone)dipalladium
  • a ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or Xantphos are added to compound a30, and the mixture is reacted at 50°C to 180°C, and preferably at 70°C to 150°C, for 0.1 hours to 8 hours, and preferably 0.5 to 2 hours, whereby compound a64
  • compound A-13 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-14 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , R 51 , and R 6 have the same meaning as described above, and R 5f is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • toluene, benzene or the like, or a mixed solvent of those and water, diphenylphosphoryl azide and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine are added to compound a57, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 80°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, and thereafter potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is added, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a65 can be obtained.
  • diphenylphosphoryl azide and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine
  • a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine or N-methylmorpholine is added to compound a65 as a base, and then an acylating reagent such as an acid chloride or acid anhydride that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a66 can be obtained.
  • a solvent such as dichloromethane, dichloroethane or THF
  • pyridine triethylamine or N-methylmorpholine
  • a base such as sodium hydride, tert-butoxypotassium or lithium diisopropylamide
  • R 51 -I, R 51 -Br, R 51 -Cl or the like that is commercially available or synthesized by a known method are added to compound a66, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 3 hours, and preferably 0.5 hours to 1 hour, whereby compound a67 can be obtained.
  • compound A-15 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-16 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 5g is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, and R 5g' is a hydrogen atom.
  • R 5g -NCO that is commercially available or synthesized by a known method is added to compound a65, and the mixture is reacted at 25°C to 120°C, and preferably at 60°C to 80°C, for 0.5 hours to 4 hours, and preferably 1 hour to 2 hours, whereby compound a68 can be obtained.
  • a base such as triethylamine or N-methylmorpholine is added to compound a65, and reacted with triphosgene, thereby synthesizing an isocyanate form in the system.
  • R 5g NH 2 that is commercially available or synthesized by a known method is added without taking out the isocyanate form from the reaction mixture, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 2 hours, whereby compound a68 can be obtained.
  • compound A-17 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-18 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , R 51 , and R 6 have the same meaning as described above, and R 5h is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • a substituted sulfonyl chloride that is commercially available or synthesized by a known method is added to compound a65, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 70°C, for 1 hour to 24 hours, and preferably 5 hours to 10 hours, whereby compound a69 can be obtained.
  • a base such as sodium carbonate, potassium carbonate or cesium carbonate is added to compound a69, and then R 51 -I, R 51 -Br, R 51 -Cl or the like that is commercially available or synthesized by a known method is added, and the mixture is reacted at 0°C to 80°C, and preferably at 25°C to 50°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound a70 can be obtained.
  • a base such as sodium carbonate, potassium carbonate or cesium carbonate
  • compound A-19 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-20 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5i and R 5i' are each independently a hydrogen atom, formyl, carbamoyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl, substituted or unsubstituted alkynylcarbamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstit
  • an acid such as acetic acid or trifluoroacetic acid is added to compound a65, and an aldehyde or ketone that is commercially available or synthesized by a known method is sequentially added, and the mixture is stirred at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, and thereafter, a reducing agent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 is added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, whereby compound a71 can be obtained.
  • a reducing agent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 is added
  • compound A-21 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-22 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and L 13 is halogen.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite is added to compound a65, and then a cupric halide such as cupric chloride, cupric bromide or cupric iodide is sequentially added, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 50°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound a72 can be obtained as a chloride, a bromide or an iodide, respectively.
  • compound A-23 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-24 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite is added to compound a65, and then a cyanide such as cuprous cyanide, sodium cyanide or potassium cyanide is added, and the mixture is reacted at 0°C to 100°C, and preferably at 40°C to 70°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound a73 can be obtained.
  • compound A-25 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-26 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a diazotization reagent such as tort-butyl nitrite or isopentyl nitrite is added to compound a65, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 70°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a74 can be obtained as a deamination product.
  • compound A-27 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-28 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , and R 6 have the same meaning as described above, and R 5j and R 5j' are each independently substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, wherein R 5j and R 5j' may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • Compound a65 is suspended in concentrated hydrochloric acid, and diazotized with sodium nitrite according to a known method, and then sulfurous acid and an acetic acid solution of cuprous chloride are added, and the mixture is reacted at -20°C to 20°C, and preferably at -5°C to 10°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound a75 can be obtained.
  • compound a75 can be obtained as well by using thionyl chloride, instead of sulfurous acid and the acetic acid solution of cuprous chloride.
  • a base such as triethylamine, N-methylmorpholine or pyridine is added to compound a75, and then an amine that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound a76 can be obtained.
  • compound A-29 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-30 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , R 6 , and L 13 have the same meaning as described above, and R 5k is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • R 5k -OK or R 5k -ONa that is commercially available or prepared by a known method is added to compound a72, and the mixture is reacted at 20°C to 200°C, and preferably at 50°C to 100°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound a77 can be obtained.
  • compound A-31 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-32 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2' , R 3 , R 4 , R 6 , and L 13 have the same meaning as described above, and R 5m is a substituted or unsubstituted aromatic carbocyclic group.
  • a base such as potassium carbonate, sodium carbonate or cesium carbonate is added to compound a72, and then R 5m SH that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.1 hours to 12 hours, and preferably 0.5 hours to 3 hours, whereby compound a78 can be obtained.
  • mCPBA is added to compound a78, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 25°C, for 0.1 hours to 3 hours, and preferably 0.5 hours to 2 hours, whereby compound a79 can be obtained.
  • compound a79 can be obtained by adding oxone to compound a78 in a mixed solvent of a solvent such as acetone or tetrahydrofuran and water, and reacting the mixture at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours.
  • a solvent such as acetone or tetrahydrofuran and water
  • compound A-33 can be obtained in the same manner as in the thirty second to thirty fourth steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound A-34 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine or N-methylmorpholine is added to compound A-1 or compound A-3 as a base, and then an acylating reagent such as an acid chloride or acid anhydride that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound B-1 can be obtained.
  • a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine or N-methylmorpholine is added to compound A-1 or compound A-3 as a base
  • an acylating reagent such as an acid chloride or acid anhydride that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at -20°
  • compound B-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 72 -I, R 72 -Br, R 72 -Cl or the like that is commercially available or synthesized by a known method are added to compound B-1, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 3 hours, and preferably 0.5 hours to 1 hour, whereby compound B-3 can be obtained.
  • compound B-4 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a base such as pyridine, lutidine or triethylamine
  • a trifluoromethanesulfonylating reagent such as trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride or N-phenylbistrifluoromethanesulfonimide or a nonaflating reagent such as nonafluorobutanesulfonyl chloride or nonafluorobutanesulfonic anhydride are added to compound a29, and the mixture is reacted at -50°C to 50°C, and preferably at -30°C to 30°C, for 0.1 hours to 4 hours, and preferably 0.5 hours to 1 hour, whereby compound b1 can be obtained.
  • Compound b2 can be obtained by a coupling reaction of compound b1 with R 5 -Y-L 2 .
  • Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, and the like are exemplified.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf) 2 Cl 2 or Pd(dtbpf)
  • a base such as potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate, and boronic acid, a boronic acid ester, an alkyltin or a zinc halide that is commercially available or prepared by a known method are added to compound b1, and the mixture is reacted under a nitrogen atmosphere at 0°C to 150°C, and preferably at 60°C to 120°C, for 0.5 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound b2 can be obtained.
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide is added to compound b2, and the mixture is reacted under a hydrogen atmosphere and under 1 to 10 atmospheres, and preferably 2 to 5 atmospheres, at 0°C to 60°C, and preferably at 20°C to 40°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound b3 can be obtained.
  • a metal such as iron, zinc or tin is added to compound b2, under acidic conditions of hydrochloric acid or acetic acid, under alkaline conditions of potassium hydroxide or sodium hydroxide, or under neutral conditions of ammonium chloride, and the mixture is reacted at 0°C to 120°C, and preferably at 25°C to 80°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound b3 can be also obtained.
  • a solvent such as dichloromethane, dichloroethane, acetonitrile or DMF
  • bromine or a halogenating reagent such as NBS, NCS and NIS
  • the mixture is reacted at -30°C to 50°C, and preferably at -10°C to 20°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound b4 can be obtained.
  • L 3 is chloro or iodine
  • the mixture is reacted at 10°C to 150°C, and preferably at 60°C to 120°C, for 0.5 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound b4 can be obtained.
  • compound b5 can be obtained in the same manner as in the first step.
  • compound B-1 can be obtained in the same manner as in the sixth step.
  • compound B-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound B-3 can be obtained in the same manner as in the third step.
  • compound B-4 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a base such as triethylamine, N-methylmorpholine or DIEA and a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide are added to compound b1, and the mixture is reacted under a hydrogen atmosphere and under 1 to 10 atmospheres, and preferably 2 to 5 atmospheres, at 0°C to 60°C, and preferably at 20°C to 40°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound b6 can be obtained.
  • a base such as triethylamine, N-methylmorpholine or DIEA
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide
  • compound b6 can be also obtained by adding formic acid, a base such as triethylamine or tributylamine, a ligand such as triphenylphosphine, dppf or dppp, and a palladium catalyst such as Pd(OAc) 2 , Pd(PPh 3 ) 4 or bistriphenylphosphine palladium dichloride to compound b1, in a solvent such as toluene, DMF or dioxane, and reacting the mixture at 20°C to 200°C, and preferably at 60°C to 120°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours.
  • a base such as triethylamine or tributylamine
  • a ligand such as triphenylphosphine, dppf or dppp
  • a palladium catalyst such as Pd(OAc) 2 , Pd(PPh 3 ) 4 or bistriphenylphos
  • compound b7 can be obtained in the same manner as in the eighth step.
  • compound b8 can be obtained in the same manner as in the sixth step.
  • compound B-1 can be obtained in the same manner as in the ninth step.
  • compound b10 can be obtained in the same manner as in the fifth step in "27) Synthesis of Compounds K-1 and K-2 (Phenol Derivatives)" described below.
  • compound b11 can be obtained in the same manner as in the twelfth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound b12 can be obtained in the same manner as in the thirteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound b13 can be obtained in the same manner as in the first step.
  • compound B-1 can be obtained in the same manner as in the fourth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 71 -NCO that is commercially available or synthesized by a known method is added to compound A-1 or compound A-3, and the mixture is reacted at 25°C to 120°C, and preferably at 60°C to 80°C, for 0.5 hours to 4 hours, and preferably 1 hour to 2 hours, whereby compound C-1 can be obtained.
  • a base such as triethylamine or N-methylmorpholine is added to compound A-1 or compound A-3, and reacted with triphosgene, thereby synthesizing an isocyanate form in the system.
  • R 71 NH 2 that is commercially available or synthesized by a known method is added without taking out the isocyanate form from the reaction mixture, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 2 hours, whereby compound C-1 can be obtained.
  • compound C-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound C-1 and compound C-2 can be obtained from compound b1, in the same manner as in the sixth to eleventh steps in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" described above (however, among the above steps, the ninth step in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" is replaced with the first step in “19) Synthesis of Compounds C-1 and C-2 (Urea Derivatives)").
  • Compound C-1 in which R 1 and R 6 are methyl, and R 5 is -O-R 5k (R 5k has the same meaning as described above) can be obtained from compound b9, in the same manner as in the eighteenth to twenty second steps in "18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" described above (however, among the above steps, the twenty first step in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" is replaced with the first step in "19) Synthesis of Compounds C-1 and C-2 (Urea Derivatives)").
  • a substituted sulfonyl chloride that is commercially available or synthesized by a known method is added to compound A-1 or compound A-3, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 70°C, for 1 hour to 24 hours, and preferably 5 hours to 10 hours, whereby compound D-1 can be obtained.
  • compound D-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a base such as sodium carbonate, potassium carbonate or cesium carbonate is added to compound D-1, and then R 72 -I, R 72 -Br, R 72 -Cl or the like that is commercially available or synthesized by a known method is added, and the mixture is reacted at 0°C to 80°C, and preferably at 25°C to 50°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound D-3 can be obtained.
  • compound D-4 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compounds D-1, D-2, D-3 and D-4 can be obtained from compound b1, in the same manner as in the sixth to thirteenth steps in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" described above (however, among the above steps, the ninth step and the twelfth step in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" are replaced with the first step and the third step, respectively, in “20) Compounds D-1, D-2, D-3 and D-4 (Sulfonamide Derivatives)").
  • Compound D-1 in which R 1 and R 6 are methyl, and R 5 is -O-R 5k (R 5k has the same meaning as described above) can be obtained from compound b9, in the same manner as in the eighteenth to twenty second steps in "18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" described above (however, among the above steps, the twenty first step in “18) Synthesis of Compounds B-1, B-2, B-3, and B-4 (Amide Derivatives)" is replaced with the first step in "20) Compounds D-1, D-2, D-3 and D-4 (Sulfonamide Derivatives)").
  • an acid such as acetic acid or trifluoroacetic acid is added to compound A-1 or compound A-3, and an aldehyde or ketone that is commercially available or synthesized by a known method is sequentially added, and the mixture is stirred at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, and thereafter, a reducing agent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 is added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, whereby compound E-1 can be obtained.
  • a reducing agent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 is added
  • compound E-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Y have the same meaning as described above, and L 14 is halogen.
  • R 2 is OR 2' , and R 2' has the same meaning as described above.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite is added to compound A-1 or compound A-3, and then a cupric halide such as cupric chloride, cupric bromide or cupric iodide is sequentially added, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 50°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound F-1 can be obtained as a chloride, a bromide or an iodide, respectively.
  • compound F-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite is added to compound A-1 or compound A-3, and then a cyanide such as cuprous cyanide, sodium cyanide or potassium cyanide is added, and the mixture is reacted at 0°C to 100°C, and preferably at 40°C to 70°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound G-1 can be obtained.
  • compound G-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite is added to compound A-1 or compound A-3, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 70°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound H-1 can be obtained as a deamination product.
  • compound H-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 14 , and Y have the same meaning as described above, and L 15 is alkyl or benzyl (however, L is benzyl in the second step)
  • an alkyl alcohol such as methanol or ethanol or a benzyl alcohol, or a mixed solvent of these alcohols and dimethylformamide, dimethylsulfoxide or the like
  • a base such as triethylamine, N-methylmorpholine or pyridine
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 or PdCl 2 (dppf) is added, and the reaction mixture is well degassed, and reacted under a carbon monoxide atmosphere at 30°C to 120°C, and preferably at 70°C to 100°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby compound i1 can be obtained.
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide is added to compound i1 in which L 15 is benzyl, and the mixture is reacted under a hydrogen atmosphere at 0°C to 60°C, and preferably at 20°C to 40°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound I-1 can be obtained.
  • compound I-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is added to compound I-1, and an additive such as 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazol or N-hydroxysuccinimide is further added as necessary, and then a substituted amine (D) that is commercially available or prepared by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound J-1 can be obtained.
  • D substituted amine
  • compound J-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound k1 can be obtained in the same manner as in the twelfth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound k2 can be obtained in the same manner as in the thirteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound k3 can be obtained in the same manner as in the fourth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • Compound k3 is diazotized with sodium nitrite in dilute sulfuric acid or the like according to a known method, and the mixture is reacted at 25°C to 100°C, and preferably at 50°C to 80°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound k4 can be obtained.
  • a base such as potassium carbonate, sodium carbonate or sodium hydride is added to compound k4, and then R 71 -Cl, R 71 -Br, R 71 -I or the like that is commercially available or synthesized by a known method is added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound k5 can be obtained.
  • compound K-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • Compound k3 is suspended in concentrated hydrochloric acid, and diazotized with sodium nitrite according to a known method, and then sulfurous acid and an acetic acid solution of cuprous chloride are added, and the mixture is reacted at -20°C to 20°C, and preferably at -5°C to 10°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound 11 can be obtained.
  • compound 11 can be obtained as well by using thionyl chloride, instead of sulfurous acid and the acetic acid solution of cuprous chloride.
  • a base such as triethylamine, N-methylmorpholine or pyridine is added to compound l1, and then amine (D) that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound 12 can be obtained.
  • amine (D) that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound 12 can be obtained.
  • compound L-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • sodium sulfite and sodium bicarbonate are added to compound 11, and the mixture is reacted at 25°C to 100°C, and preferably at 50°C to 80°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, and cooled to room temperature.
  • R 71 -Cl, R 71 -Br, R 71 -I or the like that is commercially available or synthesized by a known method is added, and the mixture is reacted at 10°C to 100°C, and preferably at 40°C to 70°C, for 6 hours to 48 hours, and preferably 12 hours to 24 hours, whereby compound m1 can be obtained.
  • compound M-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y have the same meaning as described above
  • L 12 is alkyl
  • R 71a is alkyl, alkenyl, alkynyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, or a nonaromatic heterocyclic group.
  • a reducing agent such as sodium borohydride or lithium borohydride is added to compound n1, and the mixture is reacted at -20°C to 80°C, and preferably at 0°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound n2 can be obtained.
  • a base such as triethylamine, lutidine or N-methylmorpholine is added to compound n2 and methanesulfonic acid chloride, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 40°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound n3 can be obtained.
  • a palladium carbon is added to compound n4, and the mixture is reacted under a hydrogen atmosphere at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound n5 can be obtained.
  • a base such as pyridine or lutidine is added to compound n5 and an acid chloride derivative (B) that is commercially available or prepared by a known method, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound N-1 can be obtained.
  • compound N-1 can be obtained by adding 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, or the like, and/or a condensing agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine to compound n5 and a carboxylic acid derivative (C) that is commercially available or prepared by a known method, in DMF, DMA, THF, acetonitrile, or the like, or a mixed solvent thereof, and reacting the mixture at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours.
  • a condensing agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide
  • a base such as triethylamine, diisopropyleth
  • compound N-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 14 , and Y have the same meaning as described above, and R 71b and R 71c are each independently alkyl, alkenyl, or alkynyl, wherein R 71b and R 71c may be taken together with an adjacent nitrogen atom to form an aromatic heterocyclic group or a nonaromatic heterocyclic group.
  • a phosphine such as tri-tert-butylphosphine, tricyclohexylphosphine or triphenylphosphine
  • a palladium catalyst such as dibenzylideneacetone palladium, palladium acetate or dichlorobistriphenylphosphine palladium
  • a base such as N-methylmorpholine
  • an oxidizing agent such as N-methylmorpholine oxide or K 3 Fe(CN) 6 and a catalytic amount of osmium tetroxide or dipotassium osmate dihydrate are added to compound o1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound o2 can be obtained.
  • methoxymethyl triphenylphosphonium chloride is added, and the mixture is stirred at 0°C to 80°C, and preferably at 25°C to 50°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 2 hours, and thereafter, compound o3 is added, and the mixture is reacted at 0°C to 80°C, and preferably at 50°C to 60°C, for 1 hour to 48 hours, and preferably 6 hours to 24 hours, to give a methoxyvinyl form.
  • an aqueous solution of hydrochloric acid or sulfuric acid was added to the methoxyvinyl form, and the mixture is reacted at 0°C to 100°C, and preferably at 50°C to 80°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 2 hours, to give an acetaldehyde form. Furthermore, the acetaldehyde form is oxidized under Jones oxidation conditions by CrO 3 , whereby compound o4 can be obtained.
  • compound O-1 can be obtained in the same manner as in the first step in "26) Synthesis of Compounds J-1 and J-2 (Reverse Amide Derivatives)" described above.
  • compound O-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 14 , and Y have the same meaning as described above, and R 71d and R 71e are each independently alkyl, alkenyl, alkynyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, or a nonaromatic heterocyclic group.
  • compound P-1 can be obtained in the same manner as in the twenty ninth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound p1 can be obtained in the same manner as in the fortieth to forty second steps in "1) Synthesis of Compounds A-1 and A-2" described above.
  • compound P-2 can be obtained in the same manner as in the fifteenth step in "1) Synthesis of Compounds A-1 and A-2" described above.
  • R 6 has the same meaning as described above, and L 1' is substituted or unsubstituted alkyl.
  • Compound a'1 that is commercially available or synthesized by a known method is reacted with an acid halide such as acetyl chloride or acid anhydride such as acetic anhydride, by Friedel-Crafts-acylation, in a solvent of methylene chloride, dichloroethane or the like, in the presence of a Lewis acid such as aluminum chloride, at 0°C to 150°C, and preferably 60°C to 120°C, for 1 hour to 48 hours, and preferably 12 hours to 24 hours, whereby compound a'2 can be obtained.
  • an acid halide such as acetyl chloride or acid anhydride such as acetic anhydride
  • Friedel-Crafts-acylation in a solvent of methylene chloride, dichloroethane or the like
  • a Lewis acid such as aluminum chloride
  • compound a'2 is reacted at -30°C to 100°C, and preferably at 0°C to 50°C, for 0.5 hours to 48 hours, and preferably 6 hours to 24 hours, whereby compound a'3 can be obtained.
  • an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added to compound a'3, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, whereby compound a'4 can be obtained.
  • R A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group
  • L 2' is boronic acid, a boronic acid ester, an alkyltin, or a zinc halide.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or Pd(dppf) 2 Cl 2
  • R 3 , R 4 , R 5 , R 6 , Y, and L 1' have the same meaning as described above
  • R 2' is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • L 3 is halogen.
  • a toluene solution of diisobutylaluminum hydride or a tetrahydrofuran solution of lithium aluminum hydride is added to compound a'7, and the mixture is reacted at -100°C to 50°C, and preferably at -60°C to 0°C, for 0.5 hours to 10 hours, and preferably 1 hour to 3 hours, whereby compound a'8 can be obtained.
  • an oxidant such as Dess-Martin reagent, manganese dioxide or sulfur trioxide pyridine is added to compound a'8, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.5 hours to 10 hours, and preferably 1 hour to 3 hours to be oxidized, whereby compound a'9 can be obtained.
  • compound a'9 In a solvent such as methylene chloride, dichloroethane or toluene, zinc iodide and TMSCN are added to compound a'9, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a'10 can be obtained.
  • a solvent such as methylene chloride, dichloroethane or toluene, zinc iodide and TMSCN are added to compound a'9, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a'10 can be obtained.
  • an acid such as concentrated sulfuric acid or concentrated hydrochloric acid is added to compound a'10, and the mixture is reacted at 0°C to 150°C, and preferably at 80°C to 110°C, for 1 hour to 24 hours, and preferably 6 hours to 12 hours, for deprotection of a TMS group, hydrolysis to the carboxylic acid of nitrile group, followed by esterification, whereby compound a'11 can be obtained.
  • a base such as sodium hydride, potassium tert-butoxide or sodium methoxide and a halide such as R 2' -I, R 2' -Br or R 2' -Cl are added to compound a'11, and the mixture is reacted at -20°C to 100°C, and preferably at 0°C to 60°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby compound a'12 can be obtained.
  • tert-butyl ester and the like can be also obtained by adding 1 to 3 equivalents of a 70% aqueous perchloric acid solution in tert-butyl acetate, and reacting the mixture at 0°C to 60°C, and preferably at 15°C to 30°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours.
  • a catalyst such as 5% or 10% palladium carbon, palladium hydroxide or platinum dioxide is added to compound a'12, and the mixture is reacted under a hydrogen atmosphere at 0°C to 50°C, and preferably at 15°C to 25°C, for 0.1 hours to 48 hours, and preferably 1 hour to 24 hours, whereby compound a'13 can be obtained.
  • the reaction may be promoted by adding an acid such as acetic acid or hydrochloric acid.
  • an acid such as acetic acid or hydrochloric acid.
  • a metal such as iron, zinc or tin is added to compound a'12, under acidic conditions of hydrochloric acid or acetic acid, under alkaline conditions of potassium hydroxide or sodium hydroxide, or under neutral conditions of ammonium chloride, and the mixture is reacted at 0°C to 120°C, and preferably at 25°C to 80°C, for 0.1 hours to 24 hours, and preferably 1 hour to 12 hours, whereby compound a'13 can be also obtained.
  • a solvent such as dichloromethane, THF, toluene, acetonitrile or DMF
  • bromine or a halogenating reagent such as NBS, NCS and NIS is added to compound a'13, and when L 3' is bromo, the mixture is reacted at -30°C to 50°C, and preferably at -10°C to 20°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours, whereby compound a'14 can be obtained.
  • L 3' is chloro or iodine
  • the mixture is reacted at 10°C to 150°C, and preferably at 60°C to 120°C, for 0.5 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound a'14 can be obtained.
  • R 2' , R 3 , R 4 , R 5 , R 6 , R A , Y, and L 3' have the same meaning as described above, and L 10' is substituted or unsubstituted alkyl.
  • an aqueous solution of a base such as K 2 CO 3 , Na 2 CO 3 or K 3 PO 4 and (E)-3-boranyl acrylate that is commercially available or prepared by a known method are added to compound a'14, and the mixture is reacted at 50°C to 150°C, and preferably at 70°C to 130°C, for 0.1 hours to 8 hours, and preferably 0.5 to 2 hours, whereby compound a'15 can be obtained.
  • a base such as K 2 CO 3 , Na 2 CO 3 or K 3 PO 4 and (E)-3-boranyl acrylate that is commercially available or prepared by a known method
  • a palladium carbon is added to compound a'15, and the mixture is reacted under a hydrogen atmosphere at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'16 can be obtained.
  • a base such as sodium hydride or cesium carbonate, and a haloalkane that is commercially available or prepared by a known method are added to compound a'16, and the mixture is reacted at 20°C to 140°C, and preferably at 40°C to 80°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound A'-1 can be obtained.
  • compound A'-1 In a solvent such as methanol, ethanol, THF or DMSO, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is added to compound A'-1, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound A'-2 can be obtained.
  • a solvent such as methanol, ethanol, THF or DMSO
  • compound A'-2 can be obtained by adding hydrochloric acid, TFA or the like to compound A'-1, in a solvent such as methanol, ethanol, THF or DMSO, and reacting the mixture at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours.
  • a solvent such as methanol, ethanol, THF or DMSO
  • compound A'-4 can be obtained from compound A'-3 (a'16).
  • compound a'12' that is an optical isomer of compound a'12 can be synthesized from compound a'4. Furthermore, from compound a'12', compounds A'-1' and A'-2' that are optical isomers of compounds A'-1 and A'-2, respectively, can be synthesized by the method described above. wherein each definition has the same meaning as described above.
  • compound a'17 can be obtained in the same manner as in the seventh step.
  • compound a'18 can be obtained in the same manner as in the eighth step.
  • compound a'19 can be obtained in the same manner as in the ninth step.
  • compound a'20 can be obtained in the same manner as in the tenth step.
  • an oxidizing agent such as a Dess-Martin reagent or manganese dioxide is added to compound a'20, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 45°C, for 0.5 hours to 5 hours, and preferably 1 hour to 3 hours, whereby compound a'21 can be obtained.
  • a (R)-CBS reagent is added to compound a'21 as an asymmetric source, and a reducing agent such as catechol borane or 9-borabicyclo[3.3.1]nonane is sequentially added, and the mixture is reacted at -50°C to 0°C, and preferably at -35°C to -10°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a'22 can be obtained.
  • a reducing agent such as catechol borane or 9-borabicyclo[3.3.1]nonane
  • compound a'23 can be obtained in the same manner as in the eleventh step.
  • Compound a'12' that is an optical isomer of compound a'12 can be obtained from compound a'23 in the same manner as in the fourth to sixth steps.
  • compound a'24 can be obtained in the same manner as in the eleventh step.
  • compound a'25 can be obtained in the same manner as in the seventeenth step.
  • Compound a'26 can be synthesized by condensing compound a'25 with an enantiopure chiral auxiliary compound like R-(+)-4-benzyl-2-oxazolidinone (compound (A)) to produce a diastereomeric mixture and separating the diastereomeric mixture by silica gel column chromatography.
  • compound a'25 is dissolved in a solvent such as anhydrous dichloromethane, anhydrous chloroform or anhydrous THF, and thereafter a small amount of anhydrous DMF was added, and a chlorinating reagent such as thionyl chloride or oxalyl chloride is added dropwise at -30°C to 50°C, and preferably at -10°C to 20°C.
  • a solvent such as anhydrous dichloromethane, anhydrous chloroform or anhydrous THF
  • a chlorinating reagent such as thionyl chloride or oxalyl chloride is added dropwise at -30°C to 50°C, and preferably at -10°C to 20°C.
  • the mixture was stirred at -30°C to 50°C, and preferably at -10°C to 20°C, for 0.1 hours to 10 hours, and preferably 0.5 hours to 2 hours and concentrated, and the obtained foamy solid is dissolved in anhydrous tetrahydrofuran, anhydrous dichloromethane, or the like.
  • a solution of anhydrous tetrahydrofuran, anhydrous dichloromethane or the like of compound (A) is stirred at -100°C to 30°C, and preferably at -80°C to 60°C, a n-BuLi/hexane solution is added, and the mixture is stirred at -100°C to -30°C, and preferably at -80°C to -60°C, for 0.1 hours to 1 hour, and preferably 0.1 hours to 0.5 hours, and is further stirred at -20°C to 60°C, and preferably at 0°C to 30°C, for 0.1 hours to 5 hours, and preferably 0.1 hours to 2 hours.
  • the mixture is mixed with the prepared acid chloride solution at -60°C to -10°C, and preferably at -40°C to -20°C, and then heated to -10°C to 60°C, and preferably to 10°C to 30°C.
  • the mixture is quenched with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane, and then separated and purified by silica gel chromatography, whereby compound a'26 can be obtained.
  • a mixed liquid of hydrogen peroxide and an aqueous solution of lithium hydroxide is added to compound a'26, the mixture is reacted at -20°C to 10°C, and preferably at -10°C to 10°C, to obtain a carboxylate form, and thereafter, the carboxylate form is esterified by a diazomethane/diethyl ether solution or the like, whereby compound a'23 can be obtained.
  • a'27 that is commercially available or synthesized by a known method is added, in a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling, and the mixture is reacted at -20°C to 60°C, and preferably at 0°C to 25°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, whereby a nitro compound can be obtained.
  • a solvent such as concentrated sulfuric acid or acetic acid, nitric acid, fuming nitric acid or the like under ice-cooling
  • This compound is reacted in a solvent such as thionyl chloride and phosphorus oxychloride, at 20°C to 120°C, and preferably at 80°C to 100°C, for 0.5 hours to 6 hours, and preferably 1 hour to 3 hours, and the solvent is concentrated under reduced pressure, whereby a crude acid chloride can be obtained.
  • a solvent such as thionyl chloride and phosphorus oxychloride
  • a solvent such as thionyl chloride and phosphorus oxychloride
  • compound a'29 can be obtained in the same manner as in the fourth step.
  • compound a'30 can be obtained in the same manner as in the twelfth step.
  • compound a'31 can be obtained in the same manner as in the thirteenth step.
  • compound a'32 can be obtained in the same manner as in the fourteenth to sixteenth steps.
  • compound a'33 can be obtained in the same manner as in the thirteenth step.
  • compound a'34 can be obtained in the same manner as in the fourth step.
  • compound A-1 can be obtained in the same manner as in the seventh to eleventh steps.
  • compound A-1' that is an optical isomer of compound A-1 can be synthesized from compound a'28.
  • R 2' , R 3 , R 4 , R 5 , R 6 , R A , Y, and L 3' have the same meaning as described above, L 6' is halogen, and L 7' is halogen.
  • compound a'35 can be obtained in the same manner as in the eighteenth to twenty fourth steps.
  • compound a'36 can be obtained in the same manner as in the thirty first step.
  • compound a'37 can be obtained in the same manner as in the thirty second step.
  • compound A'-1' that is an optical isomer of compound A'-1 can be obtained from compound a'38 in the same manner as in the fourteenth to sixteenth steps.
  • Compound a'13' that is an optical isomer of compound a'13 can be obtained from compound a'39 in the same manner as in the thirty sixth step.
  • R 3 , R 6 , R A , L 1' , and L 5' have the same meaning as described above, and R 5a and R 5a' are each independently substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, wherein R 5a and R 5a' may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or PdCl 2 (dppf) 2
  • a base such as triethylamine or N-methylmorpholine
  • allyl alcohol is added to compound a'33, and the mixture is reacted under a carbon monoxide atmosphere at 0°C to 150°C, and preferably at 50°C to 100°C, for 1 hour to 24 hours, and preferably 3 hours to 12 hours, whereby an allyl ester form can be synthesized.
  • R 3 , R 6 , R A , and L 1' have the same meaning as described above, R 5b is alkyl, and L 8' is halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, halo alkyloxy, alkyloxyalkyl, alkyloxyalkyl
  • a base such as sodium hydride or cesium carbonate, and halogenated alkyl that is commercially available or prepared by a known method are added to compound a'34-4, and the mixture is reacted at 20°C to 140°C, and preferably at 40°C to 80°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound a'34-5 can be obtained.
  • R 5c is alkyl, alkenyl, alkynyl, an aromatic carbocyclic group, a nonaromatic carbocyclic group, an aromatic heterocyclic group, or a nonaromatic heterocyclic group
  • L 9' is alkyl
  • a base such as triethylamine, diisopropylethylamine or N-methylmorpholine, and isobutyl chloroformate, pivaloyl chloride, or the like are added to compound a'34-2, and the mixture is reacted at -20°C to 60°C, and preferably at -5°C to 20°C, for 0.5 hours to 24 hours, and preferably 1 hour to 4 hours, whereby compound a'34-6 can be obtained.
  • a base such as triethylamine, diisopropylethylamine or N-methylmorpholine, and isobutyl chloroformate, pivaloyl chloride, or the like
  • a reducing agent such as sodium borohydride or lithium borohydride is added to compound a'34-6, and the mixture is reacted at -20°C to 80°C, and preferably at 0°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'34-7 can be obtained.
  • a base such as triethylamine, lutidine or N-methylmorpholine is added to compound a'34-7, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 40°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'34-8 can be obtained.
  • a palladium carbon is added to compound a'34-9, and the mixture is reacted under a hydrogen atmosphere at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'34-10 can be obtained.
  • an acid chloride derivative (B) that is commercially available or prepared by a known method and a base such as pyridine or lutidine are added to compound a'34-10, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'34-11 can be obtained.
  • compound a'34-11 can be also obtained by adding a carboxylic acid derivative (C) that is commercially available or prepared by a known method and a condensing agent such as 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, cyclohexylcarbodiimide or diisopropylcarbodiimide, and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine to compound a'34-10, in DMF, DMA, THF, acetonitrile, or the like, or a mixed solvent thereof, and reacting the mixture at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours.
  • C carboxylic acid derivative
  • a condensing agent such as 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, cyclohexylcarbodiimide or diisopropyl
  • R 3 , R 6 , R A , L 1' , and L 5' have the same meaning as described above, and R 5d is substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • a phosphine such as tri-tert-butylphosphine, tricyclohexylphosphine or triphenylphosphine, a catalyst such as dibenzylideneacetone palladium, palladium acetate or dichlorobistriphenylphosphine palladium, and a base such as N-methylmorpholine are added to compound a'33, and the mixture is reacted with ethylene gas at 30°C to 180°C, and preferably at 50°C to 150°C, for 1 hour to 48 hours, and preferably 4 hours to 24 hours, whereby compound a'34-12 can be obtained.
  • ethylene gas at 30°C to 180°C, and preferably at 50°C to 150°C, for 1 hour to 48 hours, and preferably 4 hours to 24 hours, whereby compound a'34-12 can be obtained.
  • an oxidizing agent such as N-methylmorpholine oxide or K 3 Fe(CN) 6 and a catalytic amount of osmium tetroxide or dipotassium osmate dihydrate are added to compound a'34-12, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound a'34-13 can be obtained.
  • a mixed solvent of a buffer such as an aqueous sodium dihydrogen phosphate solution or a THF solution thereof and tert-butyl alcohol or the like
  • sodium chlorite, and amide sulfate, 2-methyl-2-butene, and the like are added to compound a'34-14, and the mixture is reacted at 0°C to 80°C, and preferably at 0°C to 50°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound a'34-15 can be obtained.
  • a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is added to compound a'34-15, and an additive such as 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazol or N-hydroxysuccinimide is further added as necessary, and then a substituted amine (D) that is commercially available or prepared by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound a'34-16 can be obtained.
  • D substituted amine
  • R 3 , R 6 , R A , L 1' , and L 5' have the same meaning as described above, and R 5e and R 5e' are each independently a hydrogen atom, formyl, carbamoyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl, substituted or unsubstituted alkynylcarbamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubsti
  • a base such as sodium carbonate, potassium carbonate, cesium carbonate or potassium phosphate, a substituted amine (F) that is commercially available or prepared by a known method
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf) 2 Cl 2 or tris(dibenzylideneacetone)dipalladium
  • a ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or Xantphos are added to compound a'33, and the mixture is reacted at 50°C to 180°C, and preferably at 70°C to 150°C, for 0.1 hours to 8 hours, and preferably 0.5 to 2 hours, whereby compound a
  • R 3 , R 51 , R 6 , R A , and L 1' have the same meaning as described above, and R 5f is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • toluene, benzene or the like, or a mixed solvent of those and water, diphenylphosphoryl azide and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine are added to compound a'34-2, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 80°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, and thereafter, potassium hydroxide, sodium hydroxide, lithium hydroxide or the like is added, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 1 hour to 24 hours, and preferably 2 hours to 6 hours, whereby compound a'34-18 can be obtained.
  • diphenylphosphoryl azide and a base such as triethylamine, diisopropylethylamine or N-methylmorpholine
  • a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine or N-methylmorpholine is added to compound a'34-18 as a base, and then an acylating reagent such as an acid chloride or acid anhydride that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a'34-19 can be obtained.
  • acylating reagent such as an acid chloride or acid anhydride that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 20°C, for 0.1 hours to 6 hours, and preferably 1 hour to 3 hours, whereby compound a'34-19 can be obtained.
  • a base such as sodium hydride, tert-butoxypotassium or lithium diisopropylamide
  • R 51 -I, R 51 -Br, R 51 -Cl or the like that is commercially available or synthesized by a known method are added to compound a'34-19, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 3 hours, and preferably 0.5 hours to 1 hour, whereby compound a'34-20 can be obtained.
  • R 3 , R 6 , R A , and L 1' have the same meaning as described above, and R 5g is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • R 5g -NCO that is commercially available or synthesized by a known method is added to compound a'34-18, and the mixture is reacted at 25°C to 120°C, and preferably at 60°C to 80°C, for 0.5 hours to 4 hours, and preferably 1 hour to 2 hours, whereby compound a'34-21 can be obtained.
  • a base such as triethylamine or N-methylmorpholine is added to compound a'34-18, and reacted with triphosgene, thereby synthesizing an isocyanate form in the system.
  • R 5g NH 2 that is commercially available or synthesized by a known method is added without taking out the isocyanate form from the reaction mixture, and the mixture is reacted at 0°C to 50°C, and preferably at 20°C to 35°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 2 hours, whereby compound a'34-21 can be obtained.
  • R 3 , R 51 , R 6 , R A , and L 1' have the same meaning as described above, and R 5h is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • a substituted sulfonyl chloride that is commercially available or synthesized by a known method is added to compound a'34-18, and the mixture is reacted at 20°C to 100°C, and preferably at 50°C to 70°C, for 1 hour to 24 hours, and preferably 5 hours to 10 hours, whereby compound a'34-22 can be obtained.
  • a base such as sodium carbonate, potassium carbonate or cesium carbonate is added to compound a'34-22, and then R 51 -I, R 51 -Br, R 51 -Cl or the like that is commercially available or synthesized by a known method is added, and the mixture is reacted at 0°C to 80°C, and preferably at 25°C to 50°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound a'34-23 can be obtained.
  • each definition has the same meaning as described above.
  • R 3 , R 6 , R A , and L 1' have the same meaning as described above, and R 5i and R 5i' are each independently a hydrogen atom, formyl, carbamoyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl, substituted or unsubstituted alkynylcarbamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alky
  • an acid such as acetic acid or trifluoroacetic acid and an aldehyde or ketone that is commercially available or synthesized by a known method are added to compound a'34-18, and the mixture is stirred at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, and thereafter, a reducing agent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 is added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours, whereby compound a'34-25 can be obtained.
  • each definition has the same meaning as described above.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite and a cyanide such as cuprous cyanide, sodium cyanide or potassium cyanide are added to compound a'34-18, and the mixture is reacted at 0°C to 100°C, and preferably at 40°C to 70°C, for 1 hour to 12 hours, and preferably 3 hours to 6 hours, whereby compound a'34-26 can be obtained.
  • a diazotization reagent such as tert-butyl nitrite or isopentyl nitrite
  • a cyanide such as cuprous cyanide, sodium cyanide or potassium cyanide
  • R 3 , R 6 , R A , and L 1' have the same meaning as described above, and R 5j and R 5j' are each independently substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group, wherein R 5j and R 5j' may be taken together with an adjacent nitrogen atom to form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted nonaromatic heterocyclic group.
  • Compound a'34-18 is suspended in concentrated hydrochloric acid, and diazotized with sodium nitrite according to a known method, and then sulfurous acid and an acetic acid solution of cuprous chloride are added, and the mixture is reacted at -20°C to 20°C, and preferably at -5°C to 10°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound a'34-27 can be obtained.
  • compound a'34-27 can be obtained as well by using thionyl chloride, instead of sulfurous acid and the acetic acid solution of cuprous chloride.
  • a base such as triethylamine, N-methylmorpholine or pyridine is added to compound a'34-27, and then an amine that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 2 hours to 12 hours, whereby compound a'34-28 can be obtained.
  • R 3 , R 6 , R A , L 1' , and L 5' have the same meaning as described above, and R 5k is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted nonaromatic heterocyclic group.
  • R 5k -OK or R 5k -ONa that is commercially available or prepared by a known method is added to compound '33, and the mixture is reacted at 20°C to 200°C, and preferably at 50°C to 100°C, for 1 hour to 48 hours, and preferably 2 hours to 24 hours, whereby compound '34-29 can be obtained.
  • R 3 , R 6 , R A , L 1' , and L 5' have the same meaning as described above, and R 5m is a substituted or unsubstituted aromatic carbocyclic group.
  • a base such as potassium carbonate, sodium carbonate or cesium carbonate is added to compound a'33, and then R 5m SH that is commercially available or synthesized by a known method is sequentially added, and the mixture is reacted at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.1 hours to 12 hours, and preferably 0.5 hours to 3 hours, whereby compound a'34-30 can be obtained.
  • a'34-31 In a solvent such as dichloromethane or chloroform, m-chloroperoxybenzoic acid is added to compound a'34-30, and the mixture is reacted at -20°C to 50°C, and preferably at 0°C to 25°C, for 0.1 hours to 3 hours, and preferably 0.5 hours to 2 hours, whereby compound a'34-31 can be obtained.
  • a solvent such as dichloromethane or chloroform
  • compound a'34-31 can be obtained by adding oxone to compound a'34-30 in a mixed solvent of a solvent such as acetone or tetrahydrofuran and water, and reacting the mixture at 0°C to 100°C, and preferably at 25°C to 60°C, for 0.5 hours to 24 hours, and preferably 3 hours to 12 hours.
  • a solvent such as acetone or tetrahydrofuran and water
  • A'-3 and A'-4 can be also synthesized using the method shown below. wherein each definition has the same meaning as described above.
  • compound a'43 can be obtained in the same manner as in the thirteenth step.
  • an acid such as acetic acid or a base such as sodium bicarbonate, and potassium permanganate are added to compound a'43, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 60°C, for 0.25 hours to 24 hours, and preferably 0.5 hours to 2 hours, whereby compound a'44 can be obtained.
  • compound A'-3 can be obtainded in the same manner as in the fourth step.
  • compound A'-4 can be obtained in the same manner as in the seventeenth step.
  • compound a'40 In a solvent such as methylene chloride, toluene or THF, phosphorus tribromide, thionyl bromide or the like is added to compound a'8, and the mixture is reacted at -20°C to 120°C, and preferably at 0°C to 60°C, for 0.1 hours to 12 hours, and preferably 1 hour to 4 hours, whereby compound a'40 can be obtained.
  • a solvent such as methylene chloride, toluene or THF, phosphorus tribromide, thionyl bromide or the like is added to compound a'8, and the mixture is reacted at -20°C to 120°C, and preferably at 0°C to 60°C, for 0.1 hours to 12 hours, and preferably 1 hour to 4 hours, whereby compound a'40 can be obtained.
  • a palladium catalyst such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or PdCl 2 (dppf) 2
  • a base such as triethylamine or N-methylmorpholine, and R 4 OH
  • a base such as lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide or sodium hexamethyldisilazide, and an alkyl halide such as R 2 -I, R 2 -Br or R 2 -Cl are added to compound a'41, and the mixture is reacted at -70°C to 50°C, and preferably at -20°C to 20°C, for 1 hour to 24 hours, and preferably 3 hours to 10 hours, whereby compound a'42 can be obtained.
  • a base such as lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide or sodium hexamethyldisilazide
  • an alkyl halide such as R 2 -I, R 2 -Br or R 2 -Cl
  • compound A'-5 can be obtained in the same manner as in the twelfth to sixteenth steps in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • compound A'-6 can be obtained in the same manner as in the seventeenth step in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • a base such as triethylamine or diisopropylethylamine, and 1,3-dibenzyloxycarbonylamino-2-methyl-isothiourea synthesized by a known method are added to compound a'14, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 60°C, for 0.5 hours to 8 hours, and preferably 1 to 2 hours, whereby compound b'1 can be obtained.
  • a base such as triethylamine or diisopropylethylamine, and copper iodide are added to compound b'2, and the mixture is reacted at 50°C to 200°C, and preferably at 80°C to 170°C, for 0.5 hours to 8 hours, and preferably 2 to 4 hours, whereby compound B'-1 can be obtained.
  • lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like is added to compound B'-1, and the mixture is reacted at 20°C to 100°C, and preferably at 40°C to 80°C, for 0.5 hours to 8 hours, and preferably 1 to 4 hours, whereby compound B'-2 can be obtained.
  • a solvent such as DMF, DMA, THF or dioxane, or in a mixed solvent thereof, silylacetylene, a base such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 or K 3 PO 4 , a catalyst such as dibenzylideneacetone palladium, palladium acetate or dichlorobistriphenylphosphine palladium, and an additive such as lithium chloride or tetrabutylammonium chloride are added to trimethyl compound a'14, and the mixture is reacted at 20°C to 150°C, and preferably at 50°C to 120°C, for 0.5 hours to 8 hours, and preferably 1 to 2 hours, whereby compound c'1 can be obtained.
  • a base such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 or K 3 PO 4
  • a catalyst such as dibenzylideneacetone palladium, palladium acetate or dichlorobistriphenyl
  • tetrabutylammonium fluoride is added to compound c'1, and the mixture is reacted at 0°C to 80°C, and preferably at 20°C to 60°C, for 0.5 hours to 8 hours, and preferably 1 to 4 hours, whereby compound C'-1 can be obtained.
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide is added to compound C'-1, and the mixture is reacted at 20°C to 100°C, and preferably at 40°C to 80°C, for 0.5 hours to 8 hours, and preferably 1 to 4 hours, whereby compound C'-2 can be obtained.
  • compound d'1 can be obtained in the same manner as in the twelfth step in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • Compound d'1 is mixed with glycerin, nitrobenzene, and a 75% sulfuric acid aqueous solution, and the mixture is reacted at 80°C to 180°C, and preferably at 120°C to 150°C, for 1 hour to 12 hours, and preferably 2 hours to 6 hours, whereby compound d'2 can be obtained.
  • compound D'-1 can be obtained in the same manner as in the seventh to eleventh steps in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • compound D'-2 can be obtained in the same manner as in the seventeenth step in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • compound A'-3 can be obtained in the same manner as in the fourteenth to fifteenth steps in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • compound F'-1 can be obtained in the same manner as in the first step in "40) Synthesis of Compounds F'-1 to F'-6" described below.
  • phosphorus trichloride is added to compound F'-1, and the mixture is reacted at 0°C to 150°C, and preferably at 20°C to 110°C, for 0.1 hours to 8 hours, and preferably 0.5 to 2 hours, whereby compound d'3 can be obtained.
  • compound D'-3 can be obtained in the same manner as in the fourth step in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • compound D'-4 can be obtained in the same manner as in the seventeenth step in "33) Synthesis of Compounds A'-1 to A'-4" described above.
  • benzoyl isothiocyanate that is commercially available or synthesized by a known method is added to compound a'14, and the mixture is reacted at 0°C to 80°C, and preferably at 25°C to 50°C, for 0.1 hours to 6 hours, and preferably 0.5 hours to 3 hours, whereby compound e'1 can be obtained.
  • a base such as sodium hydride, potassium tert-butoxide or sodium methoxide is added to compound e'1, and the mixture is reacted at 25°C to 140°C, and preferably at 50°C to 100°C, for 0.5 hours to 12 hours, and preferably 1 hour to 6 hours, whereby compound e'2 can be obtained.
  • a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide is added to compound e'2, and the mixture is reacted at 0°C to 100°C, and preferably at 20°C to 50°C, for 0.1 hours to 24 hours, and preferably 1 hour to 6 hours, whereby compound E'-1 can be obtained.

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Claims (25)

  1. Composé représenté par la formule (I) ou l'un de ses sels pharmaceutiquement acceptables :
    Figure imgb0547
     dans lequel
    R1 représente un atome d'halogène, un groupe cyano, nitro, ou -X-R11,
    X représente une liaison simple, -O-, -S-, -NR12-, -CO-, -SO2-, -O-CO-, -CO-O-, -NR12-CO-, -CO-NR12-, -NR12-CO-O-, -NR12-CO-NR13-, -NR12-SO2-, ou -SO2-NR12-,
    R11 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    R12 et R13 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué,
    lorsque X représente -NR12-, -CO-NR12-, ou -SO2-NR12, R11 et R12 peuvent être pris conjointement avec un atome d'azote adjacent pour former un groupe hétérocyclique aromatique substitué ou non substitué ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    R2 représente indépendamment un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, alkyloxy substitué ou non substitué, alcényloxy substitué ou non substitué, alcynyloxy substitué ou non substitué, alkylsulfanyle substitué ou non substitué, alcénylsulfanyle substitué ou non substitué, ou alcynylsulfanyle substitué ou non substitué,
    n vaut 1 ou 2,
    R3 représente un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    R4 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    R5 représente un atome d'hydrogène, un groupe hydroxy, formyle, carboxy, carbamoyle, carbamoyloxy, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, alkyloxy substitué ou non substitué, alcényloxy substitué ou non substitué, alcynyloxy substitué ou non substitué, alkylsulfanyle substitué ou non substitué, alcénylsulfanyle substitué ou non substitué, alcynylsulfanyle substitué ou non substitué, alkylcarbonyle substitué ou non substitué, alcénylcarbonyle substitué ou non substitué, alcynylcarbonyle substitué ou non substitué, alkyloxycarbonyle substitué ou non substitué, alcényloxycarbonyle substitué ou non substitué, alcynyloxycarbonyle substitué ou non substitué, monoalkyl-carbamoyle substitué ou non substitué, dialkylcarbamoyle substitué ou non substitué, monoalkylcarbamoyloxy substitué ou non substitué, dialkylcarbamoyloxy substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, un groupe hétérocyclique non aromatique substitué ou non substitué, un groupe (carbocyclique aromatique)-oxy substitué ou non substitué, (carbocyclique non aromatique)-oxy substitué ou non substitué, (hétérocyclique aromatique)-oxy substitué ou non substitué, (hétérocyclique non aromatique)-oxy substitué ou non substitué, (carbocyclique aromatique)-sulfanyle substitué ou non substitué, (carbocyclique non aromatique)-sulfanyle substitué ou non substitué, (hétérocyclique aromatique)-sulfanyle substitué ou non substitué, (hétérocyclique non aromatique)-sulfanyle substitué ou non substitué, (carbocyclique aromatique)-carbonyle substitué ou non substitué, (carbocyclique non aromatique)-carbonyle substitué ou non substitué, (hétérocyclique aromatique)-carbonyle substitué ou non substitué, (hétérocyclique non aromatique)-carbonyle substitué ou non substitué, (carbocyclique aromatique)-oxycarbonyle substitué ou non substitué, (carbocyclique non aromatique)-oxycarbonyle substitué ou non substitué, (hétérocyclique aromatique)-oxycarbonyle substitué ou non substitué, (hétérocyclique non aromatique)-oxycarbonyle substitué ou non substitué, (carbocyclique aromatique)-carbamoyle substitué ou non substitué, (carbocyclique non aromatique)-carbamoyle substitué ou non substitué, (hétérocyclique aromatique)-carbamoyle substitué ou non substitué, (hétérocyclique non aromatique)-carbamoyle substitué ou non substitué, ou -NR51R52 (R51 et R52 représentent chacun indépendamment un atome d'hydrogène, un groupe formyle, carbamoyle, carboxy, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, alkylcarbonyle substitué ou non substitué, alcénylcarbonyle substitué ou non substitué, alcynylcarbonyle substitué ou non substitué, alkylcarbamoyle substitué ou non substitué, alcénylcarbamoyle substitué ou non substitué, alcynylcarbamoyle substitué ou non substitué, alkyloxycarbonyle substitué ou non substitué, alcényloxycarbonyle substitué ou non substitué, alcynyloxycarbonyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, un groupe hétérocyclique non aromatique substitué ou non substitué, (carbocyclique aromatique)-carbonyle substitué ou non substitué, (carbocyclique non aromatique)-carbonyle substitué ou non substitué, (hétérocyclique aromatique)-carbonyle substitué ou non substitué, (hétérocyclique non aromatique)-carbonyle substitué ou non substitué, (carbocyclique aromatique)-carbamoyle substitué ou non substitué, (carbocyclique non aromatique)-carbamoyle substitué ou non substitué, (hétérocyclique aromatique)-carbamoyle substitué ou non substitué, (hétérocyclique non aromatique)-carbamoyle substitué ou non substitué, (carbocyclique aromatique)-oxycarbonyle substitué ou non substitué, (carbocyclique non aromatique)-oxycarbonyle substitué ou non substitué, (hétérocyclique aromatique)-oxycarbonyle substitué ou non substitué, ou (hétérocyclique non aromatique)-oxycarbonyle substitué ou non substitué),
    Y représente une liaison simple, un groupe alkylène, alcénylène, ou alcynylène, lorsque R5 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué, Y représente une liaison simple,
    R6 représente un atome d'halogène, un groupe cyano, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, ou alkyloxy substitué ou non substitué, et
    R7 représente un atome d'halogène, un groupe cyano, nitro, ou -Z-R71,
    dans lequel Z représente une liaison simple, -O-, -S-, -NR72-, -CO-, -SO2-, -O-CO-, -CO-O-, -NR72-CO-, -CO-NR72-, -NR72-CO-O-, -NR72-CO-NR73-, -NR72-SO2-, ou -SO2-NR72-,
    R71 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    R72 et R73 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué,
    lorsque Z représente -NR72-, -CO-NR72-, ou -SO2-NR72-, R71 et R72 peuvent être pris conjointement avec un atome d'azote adjacent pour former un groupe hétérocyclique aromatique substitué ou non substitué ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    dans lequel R1 et R7 peuvent être pris conjointement avec un atome adjacent pour former le cycle A,
    le cycle A est un cycle carbocyclique aromatique, un cycle carbocyclique non aromatique, un cycle hétérocyclique aromatique, ou un cycle hétérocyclique non aromatique, et peut être substitué par 1 à 7 RA,
    RA représente indépendamment un atome d'halogène, un groupe cyano, nitro, oxo, ou -XA-RA1,
    dans lequel XA représente une liaison simple, -O-, -S-, -NRA2-, -CO-, -SO2-, -O-CO-, -CO-O-, -NRA2-CO-, -CO-NRA2-, -NRA2-CO-O-, -CO-O-NRA2-, -O-CO-NRA2-, -NRA2-O-CO-, -CO-NRA2-O-, -O-NRA2-CO-, -NRA2-CO-NRA3-, -NRA2-SO2-, ou -SO2-NRA2-,
    RA1 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué,
    RA2 et RA3 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué,
    lorsque XA représente -NRA2-, -CO-NRA2-, CO-O-NRA2-, -O-CO-NRA2-, ou -SO2-NRA2-, RA1 et RA2 peuvent être pris conjointement avec un atome d'azote adjacent pour former un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué, dans lequel hétérocyclyle aromatique signifie un groupe hétérocyclyle aromatique monocyclique de 5 à 8 chaînons, indolyle, isoindolyle, indazoryle, indolizinyle, quinoléinyle, isoquinoléinyle, cinnolinyle, phtalazinyle, quinazolinyle, naphtyridinyle, quinoxalinyle, purinyle, ptéridinyle, benzimidazolyle, benzisoxazolyle, benzoxazolyle, benzoxadiazolyle, benzisothiazolyle, benzothiazolyle, benzothiadiazolyle, benzofuryle, isobenzofuryle, benzothiényle, benzotriazolyle, imidazopyridyle, triazolopyridyle, imidazothiazolyle, pyrazinopyridazinyle, oxazolopyridinyle, thiazolopyridyle, carbazolyle, acridinyle, xanthényle, phénothiazinyle, phénoxathiinyle, phénoxazinyle et dibenzofuryle ; et dans lequel hétérocyclyle non aromatique signifie un groupe hétérocyclyle non aromatique monocyclique de 3 à 8 chaînons, indolinyle, isoindolinyle, chromanyle, isochromanyle, dihydrobenzofuryle, benzodioxazolyle, benzodioxanyle et benzomorpholinyle ;
    dans lequel les substituants des groupes « alkyle substitué ou non substitué », « alcényle substitué ou non substitué », « alcynyle substitué ou non substitué », « alkyloxy substitué ou non substitué », « alcényloxy substitué ou non substitué », « alcynyloxy substitué ou non substitué », « alkylcarbonyle substitué ou non substitué », « alcénylcarbonyle substitué ou non substitué », « alcynylcarbonyle substitué ou non substitué », « alkyloxycarbonyle substitué ou non substitué », « alcényloxycarbonyle substitué ou non substitué », « alcynyloxycarbonyle substitué ou non substitué », « alkylsulfanyle substitué ou non substitué », « alcénylsulfanyle substitué ou non substitué », « alcynylsulfanyle substitué ou non substitué », « monoalkylcarbamoyle substitué ou non substitué », ou « dialkylcarbamoyle substitué ou non substitué » sont choisis dans le groupe des substituants A dans lequel un ou plusieurs atomes de carbone au niveau de toute(s) position(s) possible(s) peuvent être substitués par un ou plusieurs substituants choisis dans le groupe des substituants A ;
    Groupe des substituants A : halogène, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyle, formyloxy, carbamoyle, sulfamoyle, sulfanyle, sulfino, sulfo, thioformyle, thiocarboxy, dithiocarboxy, thiocarbamoyle, cyano, nitro, nitroso, azido, hydrazino, uréido, amidino, guanidino, trialkylsilyle, alkyloxy, alcényloxy, alcynyloxy, halogénoalkyloxy, alkylcarbonyle, alcénylcarbonyle, alcynylcarbonyle, monoalkylamino, dialkylamino, alkylsulfonyle, alcénylsulfonyle, alcynylsulfonyle, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alcénylimino, alcynylimino, alkylcarbonylimino, alcénylcarbonylimino, alcynylcarbonylimino, alkyloxyimino, alcényloxyimino, alcynyloxyimino, alkylcarbonyloxy, alcénylcarbonyloxy, alcynylcarbonyloxy, alkyloxycarbonyle, alcényloxycarbonyle, alcynyloxycarbonyle, alkylsulfanyle, alcénylsulfanyle, alcynylsulfanyle, monoalkylcarbamoyle, dialkylcarbamoyle, monoalkylsulfamoyle, dialkylsulfamoyle, carbocyclyle aromatique substitué ou non substitué, carbocyclyle non aromatique substitué ou non substitué, hétérocyclyle aromatique substitué ou non substitué, hétérocyclyle non aromatique substitué ou non substitué, (carbocyclyle aromatique)-oxy substitué ou non substitué, (carbocyclyle non aromatique)-oxy substitué ou non substitué, (hétérocyclyle aromatique)-oxy substitué ou non substitué, (hétérocyclyle non aromatique)-oxy substitué ou non substitué, (carbocyclyle aromatique)-amino substitué ou non substitué, (carbocyclyle non aromatique)-amino substitué ou non substitué, (hétérocyclyle aromatique)-amino substitué ou non substitué, (hétérocyclyle non aromatique)-amino substitué ou non substitué, (carbocyclyle aromatique)-carbonyle substitué ou non substitué, (carbocyclyle non aromatique)-carbonyle substitué ou non substitué, (hétérocyclyle aromatique)-carbonyle substitué ou non substitué, (hétérocyclyle non aromatique)-carbonyle substitué ou non substitué, (carbocyclyle aromatique)-oxycarbonyle substitué ou non substitué, (carbocyclyle non aromatique)-oxycarbonyle substitué ou non substitué, (hétérocyclyle aromatique)-oxycarbonyle substitué ou non substitué, (hétérocyclyle non aromatique)-oxycarbonyle substitué ou non substitué, (carbocyclyle aromatique)-carbonylamino, (carbocyclyle non aromatique)-carbonylamino, (hétérocyclyle aromatique)-carbonylamino, (hétérocyclyle non aromatique)-carbonylamino, (carbocyclyle aromatique)-alkyloxy, (carbocyclyle non aromatique)-alkyloxy, (hétérocyclyle aromatique)-alkyloxy, (hétérocyclyle non aromatique)-alkyloxy, (carbocyclyle aromatique)-alkylsulfanyle, (carbocyclyle non aromatique)-alkylsulfanyle, (hétérocyclyle aromatique)-alkylsulfanyle, (hétérocyclyle non aromatique)-alkylsulfanyle, (carbocyclyle aromatique)-alkyloxycarbonyle, (carbocyclyle non aromatique)-alkyloxycarbonyle, (hétérocyclyle aromatique)-alkyloxycarbonyle, (hétérocyclyle non aromatique)-alkyloxycarbonyle, (carbocyclyle aromatique)-alkylamino, (carbocyclyle non aromatique)-alkylamino, (hétérocyclyle aromatique)-alkylamino, (hétérocyclyle non aromatique)-alkylamino, (carbocyclyle aromatique)-sulfanyle substitué ou non substitué, (carbocyclyle non aromatique)-sulfanyle substitué ou non substitué, (hétérocyclyle aromatique)-sulfanyle substitué ou non substitué, (hétérocyclyle non aromatique)-sulfanyle substitué ou non substitué, (carbocyclyle aromatique)-sulfonyle substitué ou non substitué, (carbocyclyle non aromatique)-sulfonyle substitué ou non substitué, (hétérocyclyle aromatique)-sulfonyle substitué ou non substitué, et (hétérocyclyle non aromatique)-sulfonyle substitué ou non substitué ;
    dans lequel les substituants sur chaque cycle « groupe carbocyclique aromatique substitué ou non substitué », « groupe carbocyclique non aromatique substitué ou non substitué », « groupe hétérocyclique aromatique substitué ou non substitué », « groupe hétérocyclique non aromatique substitué ou non substitué », « (carbocycle aromatique)-oxy substitué ou non substitué », « (carbocycle non aromatique)-oxy substitué ou non substitué », « (hétérocycle aromatique)-oxy substitué ou non substitué », « (hétérocycle non aromatique)-oxy substitué ou non substitué », « (carbocycle aromatique)-carbonyle substitué ou non substitué », « (carbocycle non aromatique)-carbonyle substitué ou non substitué », « (hétérocycle aromatique)-carbonyle substitué ou non substitué », « (hétérocycle non aromatique)-carbonyle substitué ou non substitué », « (carbocycle aromatique)-oxycarbonyle substitué ou non substitué », « (carbocycle non aromatique)-oxycarbonyle substitué ou non substitué », « (hétérocycle aromatique)-oxycarbonyle substitué ou non substitué », « (hétérocycle non aromatique)-oxycarbonyle substitué ou non substitué », « (carbocycle aromatique)-sulfanyle substitué ou non substitué », « (carbocycle non aromatique)-sulfanyle substitué ou non substitué », « (hétérocycle aromatique)-sulfanyle substitué ou non substitué », « (hétérocycle non aromatique)-sulfanyle substitué ou non substitué », « carbocycle aromatique », « carbocycle non aromatique », « hétérocycle aromatique », et « hétérocycle non aromatique » sont choisis dans le groupe des substituants B suivant, dans lequel un ou plusieurs atomes de carbone au niveau de toute(s) position(s) possible(s) peuvent être substitués par un ou plusieurs substituants choisis dans le groupe des substituants B suivant :
    Groupe des substituants B : halogène, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyle, carbamoyle, sulfamoyle, sulfanyle, sulfino, sulfo, thioformyle, thiocarboxy, dithiocarboxy, thiocarbamoyle, cyano, nitro, azido, hydrazino, uréido, amidino, guanidino, trialkylsilyle, alkyle, alcényle, alcynyle, halogénoalkyle, hydroxyalkyle, alkyloxy, alcényloxy, alcynyloxy, halogénoalkyloxy, alkyloxyalkyle, alkyloxyalkyloxy, alkylcarbonyle, alcénylcarbonyle, alcynylcarbonyle, monoalkylamino, dialkylamino, alkylsulfonyle, alcénylsulfonyle, alcynylsulfonyle, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alcénylimino, alcynylimino, alkylcarbonylimino, alcénylcarbonylimino, alcynylcarbonylimino, alkyloxyimino, alcényloxyimino, alcynyloxyimino, alkylcarbonyloxy, alcénylcarbonyloxy, alcynylcarbonyloxy, alkyloxycarbonyle, alcényloxycarbonyle, alcynyloxycarbonyle, alkylsulfanyle, alcénylsulfanyle, alcynylsulfanyle, monoalkylcarbamoyle, dialkylcarbamoyle, monoalkylsulfamoyle, dialkylsulfamoyle, groupe carbocyclique aromatique, groupe carbocyclique non aromatique, groupe hétérocyclique aromatique, groupe hétérocyclique non aromatique, (carbocycle aromatique)-oxy, (carbocycle non aromatique)-oxy, (hétérocycle aromatique)-oxy, (hétérocycle non aromatique)-oxy, (carbocycle aromatique)-amino, (carbocycle non aromatique)-amino, (hétérocycle aromatique)-amino, (hétérocycle non aromatique)-amino, (carbocycle aromatique)-carbonyle, (carbocycle non aromatique)-carbonyle, (hétérocycle aromatique)-carbonyle, (hétérocycle non aromatique)-carbonyle, (carbocycle aromatique)-oxycarbonyle, (carbocycle non aromatique)-oxycarbonyle, (hétérocycle aromatique)-oxycarbonyle, (hétérocycle non aromatique)-oxycarbonyle, (carbocycle aromatique)-carbonylamino, (carbocycle non aromatique)-carbonylamino, (hétérocycle aromatique)-carbonylamino, (hétérocycle non aromatique)-carbonylamino, (carbocycle aromatique)-alkyle, (carbocycle non aromatique)-alkyle, (hétérocycle aromatique)-alkyle, (hétérocycle non aromatique)-alkyle, (carbocycle aromatique)-alkyloxy, (carbocycle non aromatique)-alkyloxy, (hétérocycle aromatique)-alkyloxy, (hétérocycle non aromatique)-alkyloxy, (carbocycle aromatique)-alkylsulfanyle, (carbocycle non aromatique)-alkylsulfanyle, (hétérocycle aromatique)-alkylsulfanyle, (hétérocycle non aromatique)-alkylsulfanyle, (carbocycle aromatique)-alkyloxycarbonyle, (carbocycle non aromatique)-alkyloxycarbonyle, (hétérocycle aromatique)-alkyloxycarbonyle, (hétérocycle non aromatique)-alkyloxycarbonyle, (carbocycle aromatique)-alkyloxyalkyle, (carbocycle non aromatique)-alkyloxyalkyle, (hétérocycle aromatique)-alkyloxyalkyle, (hétérocycle non aromatique)-alkyloxyalkyle, (carbocycle aromatique)-alkylamino, (carbocycle non aromatique)-alkylamino, (hétérocycle aromatique)-alkylamino, (hétérocycle non aromatique)-alkylamino, (carbocycle aromatique)-sulfanyle, (carbocycle non aromatique)-sulfanyle, (hétérocycle aromatique)-sulfanyle, (hétérocycle non aromatique)-sulfanyle, (carbocycle non aromatique)-sulfonyle, (carbocycle aromatique)-sulfonyle, (hétérocycle aromatique)-sulfonyle, et (hétérocycle non aromatique)-sulfonyle ;
    ou dans lequel le groupe « carbocyclyle non aromatique substitué ou non substitué » ou « hétérocyclyle non aromatique substitué ou non substitué » peut être substitué par un groupe « oxo » ;
    ou dans lequel les « groupe carbocyclique non aromatique substitué ou non substitué » et « groupe hétérocyclique non aromatique substitué ou non substitué » peuvent être pontés avec un groupe alkylène, alcénylène, ou alcynylène, ou former un cycle spiro conjointement avec un autre cycle ;
    ou dans lequel les « carbocycle non aromatique » et « hétérocycle non aromatique » des groupes « (carbocycle non aromatique)-oxy substitué ou non substitué », « (hétérocycle non aromatique)-oxy substitué ou non substitué », « (carbocycle non aromatique)-carbonyle substitué ou non substitué », « (hétérocycle non aromatique)-carbonyle substitué ou non substitué », « (carbocycle non aromatique)-oxycarbonyle substitué ou non substitué », « (hétérocycle non aromatique)-oxycarbonyle substitué ou non substitué », « (carbocycle non aromatique)-sulfanyle substitué ou non substitué », et « (hétérocycle non aromatique)-sulfanyle substitué ou non substitué » peuvent être substitués par un groupe « oxo » ;
    à condition que les composés suivants soient exclus :
    Figure imgb0548
  2. Composé selon la revendication 1 ou l'un de ses sels pharmaceutiquement acceptables,
    dans lequel R1 représente un atome d'halogène, un groupe cyano, nitro, ou -X-R11 (X représente une liaison simple, -O-, -S-, -NR12-, -CO-, -SO2-, -O-CO-, -CO-O-, -NR12-CO-, -CO-NR12-, -NR12-CO-O-, NR12-CO-NR13-, -NR12-SO2-, ou -SO2-NR12-; R11 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué ; R12 et R13 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué ; lorsque X représente -NR12-, -CO-NR12-, ou -SO2-NR12-, R11 et R12 peuvent être pris conjointement avec un atome d'azote adjacent pour former un groupe hétérocyclique aromatique substitué ou non substitué ou un groupe hétérocyclique non aromatique substitué ou non substitué),
    R7 représente un atome d'halogène, un groupe cyano, nitro, ou -Z-R71 (Z représente une liaison simple, -O-, -S-, -NR72-, -CO-, -SO2-, -O-CO-, -CO-O-, -NR72-CO-, -CO-NR72-, -NR72-CO-O-, -NR72-CO-NR73-, -NR72-SO2-, ou -SO2-NR72- ; R71 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué ; R72 et R73 représentent chacun indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou alcynyle substitué ou non substitué, et lorsque Z représente -NR72-, -CO-NR72-, ou -SO2-NR72-, R71 et R72 peuvent être pris conjointement avec un atome d'azote adjacent pour former un groupe hétérocyclique aromatique substitué ou non substitué ou un groupe hétérocyclique non aromatique substitué ou non substitué).
  3. Composé selon la revendication 2 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R1 représente un atome d'hydrogène, d'halogène, un groupe cyano, alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou un groupe carbocyclique aromatique substitué ou non substitué.
  4. Composé selon la revendication 2 ou 3 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R7 représente -Z-R71, et Z représente une liaison simple, -O-, -NR72-, -SO2-, -NR72-CO-, -CO-NR72-, -NR72-CO-O, -NR72-CO-NR73-, -NR72-SO2-, ou -SO2-NR72-.
  5. Composé selon la revendication 4 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R71 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué.
  6. Composé selon la revendication 4 ou 5 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel Z représente une liaison simple, -NR72-, -NR72-CO-, -CO-NR72-, -NR72-CO-O-, -NR72-CO-NH-, -NR72-SO2-, ou -SO2-NR72-.
  7. Composé selon la revendication 6 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel Z représente une liaison simple, -NR72-, -NR72-CO-, -NR72-CO-O-, -NR72-CO-NH-, ou -NR72-SO2-.
  8. Composé selon la revendication 2 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R4 représente un atome d'hydrogène, n vaut 1, R2 représente un groupe alkyloxy substitué ou non substitué, R6 représente un groupe alkyle substitué ou non substitué, R1 représente un atome d'hydrogène, d'halogène, un groupe cyano, alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou un groupe carbocyclique aromatique substitué ou non substitué.
  9. Composé selon la revendication 2 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R4 représente un atome d'hydrogène, n vaut 1, R2 représente un groupe alkyloxy substitué ou non substitué, R6 représente un groupe alkyle substitué ou non substitué, R1 représente un atome d'hydrogène, d'halogène, un groupe cyano, alkyle substitué ou non substitué, alcényle substitué ou non substitué, ou un groupe carbocyclique aromatique substitué ou non substitué, R5 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, un groupe hétérocyclique non aromatique substitué ou non substitué, (carbocyclique aromatique)-carbamoyle substitué ou non substitué, (carbocyclique non aromatique)-carbamoyle substitué ou non substitué, ou -NR51R52 (R51 représente un groupe (carbocyclique aromatique)-carbonyle substitué ou non substitué ou (carbocyclique non aromatique)-carbonyle substitué ou non substitué, et R52 représente un atome d'hydrogène), Y représente une liaison simple, R7 représente -Z-R71, Z représente une liaison simple, -O-, -NR72-, -SO2-, -NR72-CO-, -CO-NR72-, -NR72-CO-O-, -NR72-CO-NR73-, -NR72-SO2- ou -SO2-NR72-, et R3 représente un groupe phényle substitué ou non substitué, cycloalcényle substitué ou non substitué, benzofuryle substitué ou non substitué, benzodioxolyle substitué ou non substitué, benzodioxanyle substitué ou non substitué, dihydrobenzofuryle substitué ou non substitué, chromanyle substitué ou non substitué, ou benzomorpholinyle substitué ou non substitué.
  10. Composé selon la revendication 1 ou l'un de ses sels pharmaceutiquement acceptables, représenté par la formule (II) :
    Figure imgb0549
     dans lequel m est tout nombre entier allant de 0 à 7, et les autres symboles ont la même signification que dans la revendication 1.
  11. Composé selon l'une quelconque des revendications 1, 2 et 10 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R4 représente un atome d'hydrogène.
  12. Composé selon la revendication 10 ou 11 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel n vaut 1.
  13. Composé selon l'une quelconque des revendications 10 à 12 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R2 représente un groupe alkyloxy substitué ou non substitué.
  14. Composé selon l'une quelconque des revendications 10 à 13 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel le cycle A est un cycle à cinq chaînons ou un cycle à six chaînons.
  15. Composé selon l'une quelconque des revendications 10 à 14 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel le cycle A est un cycle hétérocyclique aromatique ou un cycle hétérocyclique non aromatique.
  16. Composé selon l'une quelconque des revendications 10 à 15 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel m est tout nombre entier allant de 0 à 4.
  17. Composé selon l'une quelconque des revendications 10 à 16 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel RA représente un atome d'halogène, un groupe cyano, oxo ou -XA-RA1 (XA représente une liaison simple, -O-, -S-, -NRA2-, -CO-, -SO2-, NRA2-CO-, -CO-NRA2-, -NRA2-CO-NRA3-, -NRA2-SO2-, ou -SO2-NRA2-, RA1 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué, et RA2 et RA3 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle substitué ou non substitué).
  18. Composé selon la revendication 10 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R4 représente un atome d'hydrogène, n vaut 1, R2 représente un groupe alkyloxy substitué ou non substitué, R6 représente un groupe alkyle substitué ou non substitué, le cycle A est un cycle hétérocyclique aromatique ou un cycle hétérocyclique non aromatique à cinq chaînons ou à six chaînons, et m est tout nombre entier allant de 0 à 4.
  19. Composé selon la revendication 10 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R4 représente un atome d'hydrogène, n vaut 1, R2 représente un groupe alkyloxy substitué ou non substitué, R6 représente un groupe alkyle substitué ou non substitué, le cycle A est un cycle hétérocyclique aromatique ou un cycle hétérocyclique non aromatique à cinq chaînons ou à six chaînons, et m est tout nombre entier allant de 0 à 4, R5 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, un groupe hétérocyclique non aromatique substitué ou non substitué, (carbocyclique aromatique)-carbamoyle substitué ou non substitué, (carbocyclique non aromatique)-carbamoyle substitué ou non substitué, ou -NR51R52 (R51 représente un groupe (carbocyclique aromatique)-carbonyle substitué ou non substitué ou (carbocyclique non aromatique)-carbonyle substitué ou non substitué, et R52 représente un atome d'hydrogène), Y représente une liaison simple, RA représente indépendamment un atome d'halogène, un groupe cyano, oxo ou -XA-RA1 (XA représente une liaison simple, -O-, -S-, -NRA2-, -CO-, -SO2-, NRA2-CO-, -CO-NRA2-, -NRA2-CO-NRA3-, -NRA2-SO2-, ou -SO2-NRA2-, RA1 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué, et RA2 et RA3 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle substitué ou non substitué), et R3 représente un groupe phényle substitué ou non substitué, cycloalcényle substitué ou non substitué, benzofuryle substitué ou non substitué, benzodioxolyle substitué ou non substitué, benzodioxanyle substitué ou non substitué, dihydrobenzofuryle substitué ou non substitué, chromanyle substitué ou non substitué, ou benzomorpholinyle substitué ou non substitué.
  20. Composé selon l'une quelconque des revendications 1 à 19 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R6 représente un groupe alkyle substitué ou non substitué.
  21. Composé selon l'une quelconque des revendications 1 à 20 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R5 représente un atome d'hydrogène, un groupe alkyle substitué ou non substitué, un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, un groupe hétérocyclique non aromatique substitué ou non substitué, (carbocyclique aromatique)-carbamoyle substitué ou non substitué, ou -NR51H (R51 représente un groupe (carbocyclique aromatique)-carbonyle substitué ou non substitué), ou dans lequel R5 représente un groupe carbocyclique aromatique substitué ou non substitué, un groupe carbocyclique non aromatique substitué ou non substitué, un groupe hétérocyclique aromatique substitué ou non substitué, ou un groupe hétérocyclique non aromatique substitué ou non substitué, ou dans lequel R5 représente un atome d'hydrogène, ou dans lequel R5 représente un groupe alkylcarbamoyle substitué ou non substitué, alcénylcarbamoyle substitué ou non substitué, alkyloxy substitué ou non substitué, alcényloxy substitué ou non substitué, un groupe (carbocyclique aromatique)-carbonyle substitué ou non substitué, un groupe (carbocyclique non aromatique)-carbonyle substitué ou non substitué, un groupe (hétérocyclique aromatique)-carbonyle substitué ou non substitué, un groupe (hétérocyclique non aromatique)-carbonyle substitué ou non substitué, ou un groupe (carbocyclique non aromatique)-carbamoyle substitué ou non substitué.
  22. Composé selon l'une quelconque des revendications 1 à 21 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel Y représente une liaison simple, ou dans lequel Y représente un groupe alkylène.
  23. Composé selon l'une quelconque des revendications 1 à 22 ou l'un de ses sels pharmaceutiquement acceptables, dans lequel R3 représente un groupe phényle substitué ou non substitué, cycloalcényle substitué ou non substitué, benzofuryle substitué ou non substitué, benzodioxolyle substitué ou non substitué, benzodioxanyle substitué ou non substitué, dihydrobenzofuryle substitué ou non substitué, chromanyle substitué ou non substitué, ou benzomorpholinyle substitué ou non substitué.
  24. Composition pharmaceutique comprenant le composé selon l'une quelconque des revendications 1 à 23 ou l'un de ses sels pharmaceutiquement acceptables, où le composé
    Figure imgb0550
     n'est pas exclu.
  25. Composition pharmaceutique selon la revendication 24 destinée à être utilisée dans la prévention ou le traitement du VIH.
EP12844636.6A 2011-10-25 2012-10-25 Inhibiteur de la réplication du vih Active EP2772480B2 (fr)

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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2012015097A (es) 2010-07-02 2013-05-28 Gilead Sciences Inc Derivados de acido naft-2-ilacetico para tratar sida.
TWI458711B (zh) 2010-07-02 2014-11-01 Gilead Sciences Inc 治療性化合物
ES2742261T3 (es) 2011-04-15 2020-02-13 Hivih Inhibidores de la replicación viral, su proceso de preparación y sus usos terapéuticos
MX2013012266A (es) 2011-04-21 2013-11-22 Gilead Sciences Inc Compuestos de benzotiazol y su uso farmaceutico.
WO2013103738A1 (fr) 2012-01-04 2013-07-11 Gilead Sciences, Inc. Dérivés d'acide naphtalène acétique contre l'infection par le vih
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
SG11201401189WA (en) 2012-04-20 2014-09-26 Gilead Sciences Inc Benzothiazol- 6 -yl acetic acid derivatives and their use for treating an hiv infection
TW201441197A (zh) 2013-01-31 2014-11-01 Shionogi & Co Ｈｉｖ複製抑制劑
CA2914132A1 (fr) 2013-06-21 2014-12-24 Lupin Limited Composes heterocycliques substitues utiles en tant que modulateurs de crac
CA2914415A1 (fr) 2013-06-24 2014-12-31 Lupin Limited Derives de chromane et de chromene et leur utilisation en tant que modulateurs de crac
EP2821082A1 (fr) 2013-07-05 2015-01-07 Laboratoire Biodim Procédé de production d'un lentivirus inactivé, notamment le VIH, vaccin, kit et procédé d'utilisation
EP2821104A1 (fr) 2013-07-05 2015-01-07 Laboratoire Biodim Inhibiteurs de la réplication virale, leur procédé de préparation et leurs utilisations thérapeutiques
US9932353B2 (en) 2014-02-18 2018-04-03 Viiv Healthcare Uk (No. 5) Limited Imidazopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication
US9409922B2 (en) 2014-02-18 2016-08-09 Bristol-Myers Squibb Company Imidazopyridine macrocycles as inhibitors of human immunodeficiency virus replication
EP3152215A1 (fr) 2014-02-18 2017-04-12 ViiV Healthcare UK (No.5) Limited Macrocycles de pyrazolopyrimidine utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
US9273067B2 (en) 2014-02-19 2016-03-01 Bristol-Myers Squibb Company Pyrazolopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication
WO2015147247A1 (fr) * 2014-03-28 2015-10-01 塩野義製薬株式会社 Dérivé tricyclique présentant une activité inhibitrice de la réplication du vih
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
CN104402875A (zh) * 2014-12-25 2015-03-11 西安山川医药科技有限公司 N-(2-氨基乙基)-n′-(6-取代-2-苯并噻唑基)脲及其盐类化合物的合成方法和用途
CA2987384A1 (fr) 2015-05-29 2016-12-08 Shionogi & Co., Ltd. Derive tricyclique contenant de l'azote presentant une activite inhibitrice de la replication du vih
US20210371388A1 (en) * 2020-05-12 2021-12-02 Baruch S. Blumberg Institute Bicyclic Carboxamide with Exocyclic Urea Derivatives as Antivirals for the Treatment of HBV Infection
CN112546969B (zh) * 2020-12-07 2022-12-23 安徽贝克制药股份有限公司 催化加氢连续生产装置和利托那韦中间体的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4440785A (en) † 1980-10-30 1984-04-03 A. H. Robins Company, Inc. Methods of using 2-aminobiphenylacetic acids, esters, and metal salts thereof to treat inflammation
WO2010130034A1 (fr) † 2009-05-15 2010-11-18 Boehringer Ingelheim International Gmbh Inhibiteurs de la replication du virus de l'immunodeficience humaine
WO2015001125A1 (fr) † 2013-07-05 2015-01-08 Laboratoire Biodim Inhibiteurs de réplication virale, leur procédé de préparation et leurs utilisations thérapeutiques

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1442707A (en) * 1973-07-07 1976-07-14 Yoshitomi Pharmaceutical Substituted phenylalkanoic acids and their derivatives and pharma ceutical compositions thereof
US5244922A (en) * 1990-09-04 1993-09-14 Burzynski Stanislaw R Methods for treating viral infections
US6849605B1 (en) * 1999-03-05 2005-02-01 The Trustees Of University Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of viral infections
JP2007008816A (ja) * 2003-10-15 2007-01-18 Ube Ind Ltd 新規イソキノリン誘導体
JPWO2007020936A1 (ja) 2005-08-17 2009-02-26 第一三共株式会社 抗真菌作用二環性複素環化合物
JP5147401B2 (ja) * 2005-09-06 2013-02-20 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するインドールカルボン酸誘導体
RU2008122547A (ru) * 2005-11-07 2009-12-20 Айрм Ллк (Bm) Соединения и композиции как модуляторы арпп (активированных рецепторов пролифератора пероксисом)
WO2007056366A2 (fr) * 2005-11-07 2007-05-18 Irm Llc Composes et compositions utilises en tant que modulateurs des ppar
US8110681B2 (en) 2006-03-17 2012-02-07 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Compounds for the treatment of spinal muscular atrophy and other uses
US7939545B2 (en) 2006-05-16 2011-05-10 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
WO2007146838A2 (fr) * 2006-06-09 2007-12-21 Icos Corporation Acides phénylacétiques substitués utilisés en tant qu'antagonistes de dp-2
RU2469032C2 (ru) 2006-12-13 2012-12-10 Ф.Хоффманн-Ля Рош Аг Производные 2-(пиперидин-4-ил)-4-фенокси- или фениламинопиримидина в качестве ненуклеозидных ингибиторов обратной транскриптазы
EP2203058A4 (fr) * 2007-10-16 2011-08-31 Univ Northeastern Procédés et composés permettant la modulation de l'activité cannabinoïde
CA2705318C (fr) 2007-11-15 2013-12-31 Boehringer Ingelheim International Gmbh Inhibiteurs de la replication du virus de l'immunodeficience humaine
RU2503679C2 (ru) 2007-11-15 2014-01-10 Джилид Сайенсиз, Инк. Ингибиторы репликации вируса иммунодефицита человека
JP5269087B2 (ja) 2007-11-16 2013-08-21 ギリアード サイエンシス インコーポレーテッド ヒト免疫不全ウイルス複製のインヒビター
JP5285709B2 (ja) 2007-11-16 2013-09-11 ギリアード サイエンシス インコーポレーテッド ヒト免疫不全ウイルスの複製阻害薬
JP5583592B2 (ja) * 2007-11-30 2014-09-03 ニューリンク ジェネティクス コーポレイション Ｉｄｏ阻害剤
JP2010055911A (ja) * 2008-08-28 2010-03-11 Ushio Inc メタルハライドランプ装置
RU2011123777A (ru) * 2008-11-14 2012-12-20 ДАЙНИППОН СУМИТОМО ФАРМА Ко., ЛТД. Бифенилацетамидные производные
CN101486650A (zh) * 2009-02-20 2009-07-22 中国医学科学院药用植物研究所 具有抑制hiv活性的2-羟基苯乙酸类衍生物及其制备方法和用途
JP5390883B2 (ja) * 2009-02-26 2014-01-15 国立大学法人 熊本大学 ロキソプロフェン誘導体及びそれを含有する医薬
ES2460019T3 (es) * 2009-03-31 2014-05-13 Boehringer Ingelheim International Gmbh Derivados de 1-heterociclil-1,5-dihidro-pirazolo[3,4-d]pirimidin-4-ona y su uso como moduladores de PDE9A
GB0908394D0 (en) 2009-05-15 2009-06-24 Univ Leuven Kath Novel viral replication inhibitors
GB0913636D0 (en) 2009-08-05 2009-09-16 Univ Leuven Kath Novel viral replication inhibitors
WO2011076765A1 (fr) 2009-12-23 2011-06-30 Katholieke Universiteit Leuven Nouveaux composés antiviraux
JP2011176630A (ja) 2010-02-24 2011-09-08 Nippon Dempa Kogyo Co Ltd 無線センサーネットワーク端末
MX2012015097A (es) * 2010-07-02 2013-05-28 Gilead Sciences Inc Derivados de acido naft-2-ilacetico para tratar sida.
TWI458711B (zh) 2010-07-02 2014-11-01 Gilead Sciences Inc 治療性化合物
US8633200B2 (en) 2010-09-08 2014-01-21 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
JP5944097B2 (ja) 2010-11-02 2016-07-05 花王株式会社 口腔内清掃具
RU2564445C2 (ru) 2010-11-15 2015-10-10 ВииВ Хелткер ЮКей Лимитед Ингибиторы репликации вич
US9029391B2 (en) 2011-01-24 2015-05-12 Viiv Healthcare Uk Limited Isoquinoline compounds and methods for treating HIV
JP5018976B2 (ja) 2011-02-07 2012-09-05 株式会社日立製作所 データ記録方法および記録媒体、再生装置
EP2508511A1 (fr) 2011-04-07 2012-10-10 Laboratoire Biodim Inhibiteurs de la réplication virale, leur procédé de préparation et leurs utilisations thérapeutiques
ES2742261T3 (es) 2011-04-15 2020-02-13 Hivih Inhibidores de la replicación viral, su proceso de preparación y sus usos terapéuticos
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US8925766B2 (en) 2012-01-05 2015-01-06 Gojo Industries, Inc. Peroxide powered product dispensing system
SG11201401189WA (en) 2012-04-20 2014-09-26 Gilead Sciences Inc Benzothiazol- 6 -yl acetic acid derivatives and their use for treating an hiv infection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4440785A (en) † 1980-10-30 1984-04-03 A. H. Robins Company, Inc. Methods of using 2-aminobiphenylacetic acids, esters, and metal salts thereof to treat inflammation
WO2010130034A1 (fr) † 2009-05-15 2010-11-18 Boehringer Ingelheim International Gmbh Inhibiteurs de la replication du virus de l'immunodeficience humaine
WO2015001125A1 (fr) † 2013-07-05 2015-01-08 Laboratoire Biodim Inhibiteurs de réplication virale, leur procédé de préparation et leurs utilisations thérapeutiques

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US20140249306A1 (en) 2014-09-04
EP2772480A4 (fr) 2015-04-22
JP6099149B2 (ja) 2017-03-22
US9199959B2 (en) 2015-12-01
EP2772480B1 (fr) 2018-05-23
EP2772480A1 (fr) 2014-09-03
JPWO2013062028A1 (ja) 2015-04-02

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